Insecticidal compounds based on isoxazoline derivatives

ABSTRACT

The present invention relates to compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein A 1 , A 2 , A 3 , A 4 , G 1 , L, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3  and R 4  are as defined in claim  1 ; or a salt or N-oxide thereof. 
     Furthermore, the present invention relates to intermediates for preparing compounds of formula (I), to compositions comprising them and to methods of using them to combat and control insect, acarine, nematode and mollusc pests.

RELATED APPLICATION INFORMATION

This application is a continuation application of U.S. patentapplication Ser. No. 14/258,079, filed 22 Apr. 2014, which is acontinuation application of U.S. patent application Ser. No. 13/512,820filed May 30, 2012, which is a 371 of International Application No.PCT/EP2010/068605 filed Dec. 1, 2010, which claims priority to EP09177640.1 filed Dec. 1, 2009, and EP 10186537.6 filed Oct. 5, 2012, thecontents of which are incorporated herein by reference.

DESCRIPTION

The present invention relates to certain benzamide isoxazolines, toprocesses and intermediates for preparing them, to insecticidal,acaricidal, nematicidal and molluscicidal compositions comprising themand to methods of using them to combat and control insect, acarine,nematode and mollusc pests.

Certain isoxazoline derivatives with insecticidal properties aredisclosed, for example, in EP 1,731,512, US 2007/066617, JP 2007/008914,JP 2007/016017, WO 07/026965, JP 2007/106756, WO 07/070606, WO 07/074789and WO 07/075459.

It has now surprisingly been found that certain novel isoxazolines haveinsecticidal properties.

The present invention therefore provides a compound of formula (I):

whereinA¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen;G¹ is oxygen or sulfur;L is a single bond or C₁-C₈alkylene;R¹ is hydrogen, C₁-C₅alkyl, C₁-C₅alkylcarbonyl-, C₁-C₅alkoxy,C₁-C₅alkoxy-C₁-C₅alkyl, or C₁-C₅alkoxycarbonyl-;R² is hydrogen, C₁-C₈haloalkyl or C₁-C₈alkyl;R³ is C₁-C₅haloalkyl;R⁴ is aryl or aryl substituted by one to three R⁶, or R⁴ is heterocyclylor heterocyclyl substituted by one to three R⁶;each R⁵ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, C₂-C₅haloalkenyl,C₂-C₅alkynyl, C₂-C₅haloalkynyl, C₁-C₅alkoxy, C₁-C₈haloalkoxy,C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbon atoms together form a—CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₁-C₅haloalkyl, C₁-C₅alkoxy, or C₁-C₈haloalkoxy;Y¹ is CR⁷R⁸ or C═O;Y², Y³ and Y⁴ are independently CR⁷R⁸, C═O, N—R⁹, O, S, SO or SO₂;wherein at least two adjacent ring atoms in the ring formed by Y¹, Y²,Y³ and Y⁴ are heteroatoms;each R⁷ and R⁸ is independently hydrogen, halogen, C₁-C₅alkyl, orC₁-C₅haloalkyl;each R⁹ is independently hydrogen, cyano, cyano-C₁-C₈alkyl, C₁-C₈alkyl,C₁-C₈haloalkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkyl where one carbon atomis replaced by O, S, S(O) or SO₂, or C₃-C₅cycloalkyl-C₁-C₈alkyl,C₃-C₅cycloalkyl-C₁-C₈alkyl where one carbon atom in the cycloalkyl groupis replaced by O, S, S(O) or SO₂, or C₃-C₈cycloalkyl-C₁-C₈haloalkyl,C₁-C₈hydroxyalkyl, C₁-C₅alkoxy-C₁-C₅alkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, phenyl, phenylsubstituted by one to three R¹⁰, phenyl-C₁-C₄alkyl, phenyl-C₁-C₄alkylwherein the phenyl moiety is substituted by one to three R¹⁰, 5-6membered heteroaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkylwherein the heteroaryl moiety is substituted by one to three R¹⁰, orC₁-C₄alkyl-(C₁-C₄alkyl-O—N═)C—CH₂—;each R¹⁰ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₁-C₅haloalkyl, C₁-C₅alkoxy, or C₁-C₈haloalkoxy;or a salt or N-oxide thereof.

The compounds of formula (I) may exist in different geometric or opticalisomers or tautomeric forms. This invention covers all such isomers andtautomers and mixtures thereof in all proportions as well as isotopicforms such as deuterated compounds.

The compounds of the invention may contain one or more asymmetric carbonatoms, for example, in the —CR³R⁴— group or at the LR²Y¹Y⁴ carbon andmay exist as enantiomers (or as pairs of diastereoisomers) or asmixtures of such. Further, where any Y group is SO, the compounds of theinvention are sulfoxides, which can also exist in two enantiomericforms.

Each alkyl moiety either alone or as part of a larger group (such asalkoxy, alkylcarbonyl, or alkoxycarbonyl) is a straight or branchedchain and is, for example, methyl, ethyl, n-propyl, prop-2-yl, n-butyl,but-2-yl, 2-methyl-prop-1-yl or 2-methyl-prop-2-yl. The alkyl groups arepreferably C₁-C₆ alkyl groups, more preferably C₁-C₄ and most preferablyC₁-C₃ alkyl groups.

Alkenyl moieties can be in the form of straight or branched chains, andthe alkenyl moieties, where appropriate, can be of either the (E)- or(Z)-configuration. Examples are vinyl and allyl. The alkenyl groups arepreferably C₂-C₆, more preferably C₂-C₄ and most preferably C₂-C₃alkenyl groups.

Alkynyl moieties can be in the form of straight or branched chains.Examples are ethynyl and propargyl. The alkynyl groups are preferablyC₂-C₆, more preferably C₂-C₄ and most preferably C₂-C₃ alkynyl groups.

Halogen is fluorine, chlorine, bromine or iodine.

Haloalkyl groups (either alone or as part of a larger group, such ashaloalkoxy) are alkyl groups which are substituted by one or more of thesame or different halogen atoms and are, for example, trifluoromethyl,chlorodifluoromethyl, 2,2,2-trifluoro-ethyl or 2,2-difluoro-ethyl.

Haloalkenyl groups are alkenyl groups, respectively, which aresubstituted with one or more of the same or different halogen atoms andare, for example, 2,2-difluorovinyl or 1,2-dichloro-2-fluoro-vinyl.

Haloalkynyl groups are alkynyl groups, respectively, which aresubstituted with one or more of the same or different halogen atoms andare, for example, 1-chloro-prop-2-ynyl.

In the context of the present specification the term “aryl” refers to aring system which may be mono-, bi- or tricyclic. Examples of such ringsinclude phenyl, naphthalenyl, anthracenyl, indenyl or phenanthrenyl. Apreferred aryl group is phenyl.

The term “heteroaryl” refers to an aromatic ring system containing atleast one heteroatom and consisting either of a single ring or of two ormore fused rings. Preferably, single rings will contain up to threeheteroatoms and bicyclic systems up to four heteroatoms which willpreferably be chosen from nitrogen, oxygen and sulfur. Examples of (5-6membered) monocyclic groups include pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl, and thiadiazolyl. Examples of bicyclic groups includequinolinyl, cinnolinyl, quinoxalinyl, benzimidazolyl, benzothiophenyl,and benzothiadiazolyl. Monocyclic heteroaryl groups are preferred,preferably monocyclic rings containing 1 to 3 heterotoms selected fromO, N or S, e.g. pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl,furanyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, preferablypyridyl, pyrazolyl, furanyl, thiophenyl, thiazolyl, pyridyl being mostpreferred.

The term “heterocyclyl” is defined to include heteroaryl and in additiontheir unsaturated or partially unsaturated analogues.

Preferred values of A¹, A², A³, A⁴, G¹, L, R¹, R², R³, R⁴, Y¹, Y², Y³,Y⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰, are, in any combination, as set outbelow.

Preferably no more than two of A¹, A², A³ and A⁴ are nitrogen.

Preferably A¹ is C—H or C—R⁵, most preferably A¹ is C—R⁵.

Preferably A² is C—H or C—R⁵, most preferably A² is C—H.

Preferably A³ is C—H or N, most preferably A³ is C—H.

Preferably A⁴ is C—H or N, most preferably A⁴ is C—H.

Preferably G¹ is oxygen.

Preferably L is a single bond or C₁-C₄alkylene. More preferably L is asingle bond or CH₂, most preferably a single bond.

Preferably R¹ is hydrogen, methyl, ethyl, methylcarbonyl-, ormethoxycarbonyl-, more preferably hydrogen, methyl or ethyl, even morepreferably hydrogen or methyl, most preferably hydrogen.

Preferably R² is hydrogen or methyl, most preferably hydrogen.

Preferably R³ is chlorodifluoromethyl or trifluoromethyl, mostpreferably trifluoro-methyl.

Preferably R⁴ is aryl or aryl substituted by one to three R⁶, morepreferably R⁴ is phenyl or phenyl substituted by one to three R⁶, evenmore preferably R⁴ is phenyl substituted by one to three R⁶, morepreferably R⁴ is 3,5-bis-(trifluoromethyl)-phenyl,3-chloro-5-trifluoromethyl-phenyl, 3-bromo-5-trifluoromethyl-phenyl,3,5-dibromo-phenyl, 3,5-dichloro-phenyl, 3,4-dichloro-phenyl,3-trifluoromethyl-phenyl, 4-bromo-3,5-dichlorophenyl,4-fluoro-3,5-dichlorophenyl or 3,4,5-trichloro-phenyl, yet even morepreferably R⁴ is 3,5-dibromo-phenyl, 3,5-dichloro-phenyl,3,5-bis-(trifluoromethyl)-phenyl, 4-bromo-3,5-dichlorophenyl, or3,4,5-trichloro-phenyl, most preferably R⁴ is 3,5-dichloro-phenyl.

Preferably each R⁵ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₈alkenyl, or two R⁵ on adjacentcarbon atoms together form a —CH═CH—CH═CH— bridge, more preferablyhalogen, cyano, nitro, C₁-C₅alkyl, C₂-C₅ alkenyl, C₃-C₅cycloalkyl,C₁-C₅haloalkyl, even more preferably bromo, chloro, fluoro, cyano,nitro, methyl, ethyl, trifluoromethyl, cyclopropyl, vinyl, yet even morepreferably bromo, chloro, fluoro, cyclopropyl, trifluoromethyl, vinyl,or methyl, most preferably chloro, fluoro, or methyl.

Preferably each R⁶ is independently bromo, chloro, fluoro, cyano, nitro,methyl, ethyl, trifluoromethyl, methoxy, difluoromethoxy,trifluoromethoxy, more preferably chloro, fluoro, cyano, nitro, methyl,ethyl, trifluoromethyl, methoxy, or trifluoromethoxy, most preferablybromo, chloro, or trifluoromethyl.

Preferably Y¹ is CR⁷R⁸.

Preferably two of Y², Y³ and Y⁴ in the grouping —Y²—Y³—Y⁴_together are—S—S—, —S—SO—, —SO—SO—, —SO—SO₂—, —SO₂—SO₂—, —O—N(—R⁹)—, —O—S—, —O—SO—,—O—SO₂—, —N(—R⁹)—N(—R⁹)—, —N(—R⁹)—S—, —N(—R⁹)—S(O)—, or —N(—R⁹)—SO₂—,more preferably —S—S—, —O—N(—R⁹)—, —O—SO—, —N(—R⁹)—N(—R⁹)—, —N(—R⁹)—S,—N(—R⁹)—S(O)— or —N(—R⁹)—SO₂.

The grouping —Y²—Y³—Y⁴_may be selected from —C(R⁷)(R⁸)—N(—R⁹)—N(—R⁹)—,—C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—N(—R⁹)—S—, —C(R⁷)(R⁸)—N(—R⁹)—SO—,—C(R⁷)(R⁸)—N(—R⁹)—SO₂—, —C(R⁷)(R⁸)—O—N(—R⁹)—, —C(R⁷)(R⁸)—O—S—,—C(R⁷)(R⁸)—O—SO—, —C(R⁷)(R⁸)—O—SO₂—, —C(R⁷)(R⁸)—S—N(—R⁹)—,—C(R⁷)(R⁸)—S—O—, —C(R⁷)(R⁸)—S—S—, —C(R⁷)(R⁸)—S—SO—, —C(R⁷)(R⁸)—S—SO₂—,—C(R⁷)(R⁸)—SO—N(—R⁹)—, —C(R⁷)(R⁸)—SO—O—, —C(R⁷)(R⁸)—SO—S—,—C(R⁷)(R⁸)—SO—SO—, —C(R⁷)(R⁸)—SO—SO₂—, —C(R⁷)(R⁸)—SO₂—N(—R⁹)—,—C(R⁷)(R⁸)—SO₂—O—, —C(R⁷)(R⁸)—SO₂—S—, —C(R⁷)(R⁸)—SO₂—SO—,—C(R⁷)(R⁸)—SO₂—SO₂—, —C(═O)—N(—R⁹)—N(—R⁹)—, —C(═O)—N(—R⁹)—O—,—C(═O)—N(—R⁹)—S—, —C(═O)—N(—R⁹)—SO—, —C(═O)—N(—R⁹)—SO₂—,—C(═O)—O—N(—R⁹)—, —C(═O)—O—S—, —C(═O)—O—SO—, —C(═O)—O—SO₂—,—C(═O)—S—N(—R⁹)—, —C(═O)—S—O—, —C(═O)—S—S—, —C(═O)—S—SO—, —C(═O)—S—SO₂—,—N(—R⁹)—N(—R⁹)—C(R⁷)(R⁸), —N(—R⁹)—N(—R⁹)—C(═O), —N(—R⁹)—N(—R⁹)—S—,—N(—R⁹)—N(—R⁹)—SO—, —N(—R⁹)—N(—R⁹)—SO₂—, —N(—R⁹)—O—C(R⁷)(R⁸),—N(—R⁹)—O—C(═O)—, —N(—R⁹)—O—N(—R⁹)—, —N(—R⁹)—O—S—, —N(—R⁹)—O—SO—,—N(—R⁹)—O—SO₂—, —N(—R⁹)—S—C(R⁷)(R⁸), —N(—R⁹)—S—C(═O)—,—N(—R⁹)—S—N(—R⁹)—, —N(—R⁹)—S—O—, —N(—R⁹)—S—S—, —N(—R⁹)—S—SO—,—N(—R⁹)—S—SO₂—, —N(—R⁹)—SO—C(R⁷)(R⁸), —N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO—O—,—N(—R⁹)—SO—S—, —N(—R⁹)—SO₂—C(R⁷)(R⁸), —N(—R⁹)—SO₂—N(—R⁹)—,—N(—R⁹)—SO₂—O—, —N(—R⁹)—SO₂—S—, —O—N(—R⁹)—C(R⁷)(R⁸)—, —O—N(—R⁹)—C(═O)—,—O—N(—R⁹)—S—, —O—N(—R⁹)—SO—, —O—N(—R⁹)—SO₂—, —N(—R⁹)—O—N(—R⁹)—,—N(—R⁹)—O—S—, —N(—R⁹)—O—SO—, —N(—R⁹)—O—SO₂—, —N(—R⁹)—S—C(R⁷)(R⁸)—,—N(—R⁹)—S—C(═O)—, —N(—R⁹)—S—N(—R⁹)—, —N(—R⁹)—S—O—, —N(—R⁹)—S—S—,—N(—R⁹)—S—SO—, —N(—R⁹)—S—SO₂—, —N(—R⁹)—SO—C(R⁷)(R⁸)—,—N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO—O—, —N(—R⁹)—SO—S—,—N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —N(—R⁹)—SO₂—N(—R⁹)—, —N(—R⁹)—SO₂—O—,—N(—R⁹)—SO₂—S—, —S—N(—R⁹)—C(R⁷)(R⁸)—, —S—N(—R⁹)—C(═O)—,—S—N(—R⁹)—N(—R⁹)—, —S—N(—R⁹)—O—, —S—N(—R⁹)—S—, —S—N(—R⁹)—SO—,—S—N(—R⁹)—SO₂—, —S—O—C(R⁷)(R⁸)—, —S—O—C(═O)—, —S—O—N(—R⁹)—,—S—S—C(R⁷)(R⁸)—, —S—S—C(═O)—, —S—S—S—, —S—SO—C(R⁷)(R⁸)—, —S—SO—C(═O)—,—S—SO₂—C(R⁷)(R⁸)—, —S—SO₂—C(═O)—, —SO—N(—R⁹)—C(R⁷)(R⁸)—,—SO—N(—R⁹)—C(═O)—, —SO—N(—R⁹)—N(—R⁹)—, —SO—N(—R⁹)—O—, —SO—N(—R⁹)—S—,—SO—N(—R⁹)—SO—, —SO—O—C(R⁷)(R⁸)—, —SO—O—C(═O)—, —SO—S—C(R⁷)(R⁸)—,—SO—S—C(═O)—, —SO—S—N(—R⁹)—, —SO₂—N(—R⁹)—C(R⁷)(R⁸)—, —SO₂—N(—R⁹)—C(═O)—,—SO₂—N(—R⁹)—N(—R⁹)—, —SO₂—N(—R⁹)—O—, —SO₂—N(—R⁹)—S—, —SO₂—N(—R⁹)—SO₂—,—SO₂—O—C(R⁷)(R⁸)— and —SO₂—O—C(═O)—.

Preferably the grouping —Y²—Y³—Y⁴_is selected from—C(R⁷)(R⁸)—N(—R⁹)—N(—R⁹)—, —C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—N(—R⁹)—S—,—C(R⁷)(R⁸)—N(—R⁹)—SO₂—, —C(R⁷)(R⁸)—O—N(—R⁹)—, —C(R⁷)(R⁸)—O—SO—,—C(R⁷)(R⁸)—O—SO₂—, —C(R⁷)(R⁸)—S—N(—R⁹)—, —C(R⁷)(R⁸)—S—S—,—C(R⁷)(R⁸)—SO—O—, —C(R⁷)(R⁸)—SO₂—N(—R⁹)—, —C(R⁷)(R⁸)—SO₂—O—,—C(═O)—N(—R⁹)—N(—R⁹)—, —C(═O)—N(—R⁹)—O—, —C(═O)—N(—R⁹)—S—,—C(═O)—O—N(—R⁹)—, —C(═O)—S—N(—R⁹)—, —N(—R⁹)—N(—R⁹)—C(R⁷)(R⁸)—,—N(—R⁹)—N(—R⁹)—C(═O)—, —N(—R⁹)—O—C(R⁷)(R⁸)—, —N(—R⁹)—O—C(═O)—,—N(—R⁹)—S—C(R⁷)(R⁸)—, —N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO₂—C(R⁷)(R⁸)—,—N(—R⁹)—SO₂—N(—R⁹)—, —N(—R⁹)—SO₂—O—, —O—N(—R⁹)—C(R⁷)(R⁸)—,—O—N(—R⁹)—C(═O)—, —O—N(—R⁹)—SO—, —O—N(—R⁹)—SO₂—, —N(—R⁹)—S—C(R⁷)(R⁸)—,—N(—R⁹)—SO—C(R⁷)(R⁸)—, —N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO—O—,—N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —N(—R⁹)—SO₂—N(—R⁹)—, —N(—R⁹)—SO₂—O—,—S—N(—R⁹)—C(R⁷)(R⁸), —S—N(—R⁹)—C(═O)—, —S—S—C(R⁷)(R⁸)—,—SO—N(—R⁹)—N(—R⁹)—, —SO—O—C(R⁷)(R⁸)—, —SO₂—N(—R⁹)—C(R⁷)(R⁸)—,—SO₂—N(—R⁹)—N(—R⁹)—, —SO₂—N(—R⁹)—O— and —SO₂—O—C(R⁷)(R⁸)—. Morepreferably the grouping —Y²—Y³—Y⁴— is selected from —O—N(—R⁹)—C(═O)—,—S—S—C(R⁷)(R⁸)—, —S—SO—C(R⁷)(R⁸)—, —O—N(—R⁹)—(R⁷)(R⁸)—,—N(—R⁹)—N(—R⁹)—C(═O)—, —SO₂—N(—R⁹)— C(R⁷)(R⁸)—, —C(R⁷)(R⁸)—N(—R⁹)—O—,—C(R⁷)(R⁸)—N(—R⁹)—O—, —C(═O)—N(—R⁹)—O—, —C(═O)—N(R⁹)—O—, —O—SO—O—,—C(R⁷)(R⁸)—N(—R⁹)—SO₂, —N(—R⁹)—SO₂—O—, —SO—O—C(R⁷)(R⁸)— and—N(—R⁹)—SO—O—, even more preferably from —O—N(—R⁹)—C(═O)—,—S—S—C(R⁷)(R⁸)—, —SO₂—N(—R⁹)—C(R⁷)(R⁸)—, —C(R⁷)(R⁸)—N(—R⁹)—O—,—C(═O)—N(—R⁹)—O—, —SO—O—C(R⁷)(R⁸)— and —C(═O)—N(—R⁹)—O—, even morepreferably —O—N(—R⁹)—C(═O)— and —SO—O—C(R⁷)(R⁸)—.

In one embodiment Y² or Y⁴ is CR⁷R⁸ or C═O. According to this embodimentthe grouping —Y²—Y³—Y⁴_is preferably selected from—C(R⁷)(R⁸)—N(—R⁹)—N(—R⁹)—, —C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—N(—R⁹)—S—,—C(R⁷)(R⁸)—N(—R⁹)—SO₂—, —C(R⁷)(R⁸)—O—N(—R⁹)—, —C(R⁷)(R⁸)—O—SO—,—C(R⁷)(R⁸)—O—SO₂—, —C(R⁷)(R⁸)—S—N(—R⁹)—, —C(R⁷)(R⁸)—S—S—,—C(R⁷)(R⁸)—SO—O—, —C(R⁷)(R⁸)—SO₂—N(—R⁹)—, —C(R⁷)(R⁸)—SO₂—O—,—C(═O)—N(—R⁹)—N(—R⁹)—, —C(═O)—N(—R⁹)—O—, —C(═O)—N(—R⁹)—S—,—C(═O)—O—N(—R⁹)—, —C(═O)—S—N(—R⁹)—, —N(—R⁹)—N(—R⁹)—C(R⁷)(R⁸)—,—N(—R⁹)—N(—R⁹)—C(═O)—, —N(—R⁹)—O—C(R⁷)(R⁸)—, —N(—R⁹)—O—C(═O)—,—N(—R⁹)—S—C(R⁷)(R⁸)—, —N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —O—N(—R⁹)—C(R⁷)(R⁸)—,—O—N(—R⁹)—C(═O)—, —N(—R⁹)—S—C(R⁷)(R⁸)—, —N(—R⁹)—SO—C(R⁷)(R⁸)—,—N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —S—N(—R⁹)—C(R⁷)(R⁸), —S—N(—R⁹)—C(═O),—S—S—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)—, —SO₂—N(—R⁹)—C(R⁷)(R⁸)—, and—SO₂—O—C(R⁷)(R⁸)—. More preferably the grouping —Y²—Y³—Y⁴— is selectedfrom —S—S—C(R⁷)(R⁸)—, —O—N(—R⁹)—C(═O)—, —C(═O)—N(—R⁹)—O—,—C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—S—S—, —O—N(—R⁹)—C(R⁷)(R⁸)—,—N(—R⁹)—O—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)— and —C(R⁷)(R⁸)—N(—R⁹)—O—. Morepreferably the grouping —Y²—Y³—Y⁴— is selected from —S—S—C(R⁷)(R⁸)—,—O—N(—R⁹)—C(═O)—, —C(═O)—N(—R⁹)—O—, —SO—O—C(R⁷)(R⁸)— and—C(R⁷)(R⁸)—N(—R⁹)—O—. More preferably the grouping —Y²—Y³—Y⁴— is—O—N(—R⁹)—C(═O)— or —SO—O—C(R⁷)(R⁸)—.

In one embodiment Y² or Y⁴ is C═O. According to this embodiment thegrouping —Y²—Y³—Y⁴— is preferably selected from —C(═O)—N(—R⁹)—N(—R⁹)—,—C(═O)—N(—R⁹)—O—, —C(═O)—N(—R⁹)—S—, —C(═O)—O—N(—R⁹)—, —C(═O)—S—N(—R⁹)—,—N(—R⁹)—N(—R⁹)—C(═O)—N(—R⁹)—O—C(═O)—, —O—N(—R⁹)—C(═O)— and—S—N(—R⁹)—C(═O). More preferably the grouping —Y²—Y³—Y⁴_is selected from—O—N(—R⁹)—C(═O)— and —C(═O)—N(—R⁹)—O—.

In one embodiment Y² or Y⁴ is CR⁷R⁸. According to this embodiment thegrouping —Y²—Y³—Y⁴— is preferably selected from—C(R⁷)(R⁸)—N(—R⁹)—N(—R⁹)—, —C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—N(—R⁹)—S—,—C(R⁷)(R⁸)—N(—R⁹)—SO₂—, —C(R⁷)(R⁸)—O—N(—R⁹)—, —C(R⁷)(R⁸)—O—SO—,—C(R⁷)(R⁸)—O—SO₂—, —C(R⁷)(R⁸)—S—N(—R⁹)—, —C(R⁷)(R⁸)—S—S—,—C(R⁷)(R⁸)—SO—O—, —C(R⁷)(R⁸)—SO₂—N(—R⁹)—, —C(R⁷)(R⁸)—SO₂—O—,—N(—R⁹)—N(—R⁹)—C(R⁷)(R⁸)—, —N(—R⁹)—O—C(R⁷)(R⁸)—, —N(—R⁹)—S—C(R⁷)(R⁸)—,—N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —O—N(—R⁹)—C(R⁷)(R⁸)—, —N(—R⁹)—S—C(R⁷)(R⁸)—,—N(—R⁹)—SO—C(R⁷)(R⁸)—, —N(—R⁹)—SO₂—C(R⁷)(R⁸)—, —S—N(—R⁹)—C(R⁷)(R⁸),—S—S—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)—, —SO₂—N(—R⁹)—C(R⁷)(R⁸)— and—SO₂—O—C(R⁷)(R⁸)—. More preferably the grouping —Y²—Y³—Y⁴— is selectedfrom —S—S—C(R⁷)(R⁸)—, —C(R⁷)(R⁸)—N(—R⁹)—O—, —C(R⁷)(R⁸)—S—S—,—O—N(—R⁹)—C(R⁷)(R⁸)—, —N(—R⁹)—O—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)— and—C(R⁷)(R⁸)—N(—R⁹)—O—. More preferably the grouping Y²—Y³—Y⁴_is selectedfrom —S—S—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)— and —C(R⁷)(R⁸)—N(—R⁹)—O—.

In one embodiment Y² and Y⁴ are independently N—R⁹, O, S, SO or SO₂.According to this embodiment the grouping —Y²—Y³—Y⁴_is preferablyselected from —N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO₂—N(—R⁹)—, —N(—R⁹)—SO₂—O—,—O—N(—R⁹)—SO—, —O—N(—R⁹)—SO₂—, —N(—R⁹)—SO—N(—R⁹)—, —N(—R⁹)—SO—O—,—N(—R⁹)—SO₂—N(—R⁹)—, —N(—R⁹)—SO₂—O—, —SO—N(—R⁹)—N(—R⁹)—,—SO₂—N(—R⁹)—N(—R⁹)— and —SO₂—N(—R⁹)—O—. More preferably the groupingY²—Y³—Y⁴— is selected from —N(—R⁹)—SO₂—O—, —O—SO₂—O—,—N(—R⁹)—SO₂—N(—R⁹)—, —O—SO₂—N(—R⁹)— and —N(—R⁹)—SO₂—O—. More preferablythe grouping —Y²—Y³—Y⁴— is selected from —N(—R⁹)—SO₂—O—, —O—SO₂—O—,—N(—R⁹)—SO₂—N(—R⁹)—, and —O—SO₂—N(—R⁹)—.

In one embodiment Y¹ is CR⁷R⁸ or C═O; Y² and Y³ are independently CR⁷R⁸,C═O, N—R⁹, O, S, SO or SO₂; Y⁴ is CR⁷R⁸, C═O, SO or SO₂. Preferably Y²and Y³ are independently N—R⁹, O, S, SO, SO₂. Preferably Y² and Y³ areindependently N—R⁹, O or S. Preferably Y² is O or S. More preferably Y²is O. Preferably Y³ is N—R⁹. Preferably Y⁴ is C═O. Preferably Y³ is N—R⁹and Y⁴ is C═O. Preferably Y² is O, Y³ is N—R⁹ and Y⁴ is C═O. PreferablyY¹ is CR⁷R⁸, Y² is O, Y³ is N—R⁹ and Y⁴ is C═O.

In one embodiment Y¹ is CR⁷R⁸, Y² and Y³ are independently N—R⁹, O, S,SO or SO₂ and Y⁴ is CR⁷R⁸, C═O, SO or SO₂.

In one embodiment Y¹ is CR⁷R⁸, Y² is N—R⁹, O, S, SO or SO₂, Y³ is N—R⁹,and Y⁴ is CR⁷R⁸, C═O, SO or SO₂, preferably Y¹ is CR⁷R⁸, Y² is O or S,Y³ is N—R⁹, and Y⁴ is C═O, preferably Y¹ is CR⁷R⁸, Y² is O, Y³ is N—R⁹,and Y⁴ is C═O.

In one embodiment Y¹ is CR⁷R⁸, Y² is N—R⁹, O, S, SO or SO₂, Y³ is O orS, Y⁴ is C═O, SO, or SO₂.

In one embodiment Y¹ is C═O, Y² is N—R⁹ or O, Y³ is N—R⁹, Y⁴ is C═O, SO,or SO₂.

In one embodiment Y¹ is CR⁷R⁸, C═O, Y² is CR⁷R⁸, C═O, Y³ is N—R⁹, O orS, and Y⁴ is SO, or SO₂.

Preferably Y⁴ is CR⁷R⁸ or C═O when L is a bond, e.g. the grouping—Y²—Y³—Y⁴— is —S—S—C(R⁷)(R⁸)—, —SO—O—C(R⁷)(R⁸)— or —O—N(—R⁹)—C(═O)—,more preferably —SO—O—C(R⁷)(R⁸)— or —O—N(—R⁹)—C(═O)—.

Preferably when Y⁴ is a heteroatom, L is C₁-C₄alkylene.

Preferably when Y⁴ is NR⁹, L is C₁-C₄alkylene, in which case Y³ ispreferably NR⁹, O, S, SO or SO₂.

Preferably when Y⁴ is O, L is C₁-C₄alkylene, in which case Y³ ispreferably NR⁹.

In all embodiments at least two adjacent ring atoms in the ring formedby Y¹, Y², Y³ and Y⁴ are heteroatoms. Preferably the ring formed by Y¹,Y², Y³ and Y⁴ does not contain two adjacent oxygen atoms. In some casesthere may be no more than one oxygen ring atom in the ring formed by Y¹,Y², Y³ and Y⁴. Embodiments providing Y¹, Y², Y³, Y⁴ values may becombined with any of the values, including preferred values, of A¹, A²,A³, A⁴, G¹, L, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰.

Preferably each R⁷ is independently hydrogen, or C₁-C₅alkyl, mostpreferably hydrogen.

Preferably each R⁸ is independently hydrogen, or C₁-C₅alkyl, mostpreferably hydrogen.

Preferably R⁷ and R⁸ are both hydrogen.

Preferably each R⁹ is independently hydrogen, cyano-C₁-C₅alkyl,C₁-C₅alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl where one carbon atom inthe cycloalkyl group is replaced by O, S, S(O) or SO₂, orC₃-C₈cycloalkyl-C₁-C₈alkyl, C₃-C₈cycloalkyl-C₁-C₈alkyl where one carbonatom in the cycloalkyl group is replaced by O, S, S(O) or SO₂, orC₁-C₈haloalkyl, C₁-C₈hydroxyalkyl, C₁-C₈hydroxyalkyl, C₂-C₈alkenyl,C₂-C₈alkynyl, phenyl-C₁-C₄alkyl or phenyl-C₁-C₄alkyl wherein the phenylmoiety is substituted by one to three R¹⁰, 5-6 memberedheteoaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkyl wherein theheteroaryl moiety is substituted by one to three R¹⁰; more preferablyeach R⁹ is independently hydrogen, cyano-C₁-C₅alkyl-, C₁-C₅alkyl,C₃-C₅cycloalkyl, C₃-C₅cycloalkyl where one carbon atom in the cycloalkylgroup is replaced by O, S, S(O) or SO₂, or C₁-C₅haloalkyl,C₁-C₅hydroxyalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, phenyl-C₁-C₄alkyl orphenyl-C₁-C₄alkyl wherein the phenyl moiety is substituted by one tothree R¹⁰, 5-6 membered heteroaryl-C₁-C₄alkyl or 5-6 memberedheteroaryl-C₁-C₄alkyl wherein the heteroaryl moiety is substituted byone to three R¹⁰; even more preferably each R⁹ is independentlyhydrogen, cyano-C₁-C₆alkyl, C₁-C₆alkyl, C₃-C₆cycloalkyl, C₃-C₆cycloalkylwhere one carbon atom in the cycloalkyl group is replaced by O, S, S(O)or SO₂, or C₁-C₆haloalkyl, C₁-C₆hydroxyalkyl, C₁-C₆alkoxy-C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, phenyl-CH₂-alkyl or phenyl-CH₂— wherein thephenyl moiety is substituted by one to three R¹⁰, furanyl or furanylsubstituted by one to three R¹⁰, triazolyl or triazolyl optionallysubstituted by one to three R¹⁰; yet even more preferably each R⁹ isindependently hydrogen, C₁-C₄alkyl, C₃-C₆cycloalkyl, C₁-C₄haloalkyl,C₁-C₄hydroxyalkyl, C₁-C₄alkoxy-C₁-C₄alkyl, phenyl-CH₂-alkyl- orphenyl-CH₂— wherein the phenyl moiety is substituted by one to threeR¹⁰, furanyl or furanyl substituted by one to three R¹⁰, thietanyl,oxetanyl, oxo-thietanyl, or dioxo-thietanyl; yet even more preferablyeach R⁹ is independently methyl, ethyl, cyclopropyl, cyclobutyl,oxetanyl, thietanyl, trifluoroethyl, difluoroethyl, allyl, propargyl,cyanomethyl, benzyl, benzyl substituted by one to three R¹⁰, orpyridine-methyl- or pyridine-methyl-substituted by one to three R¹⁰.Ethyl and trifluoroethyl are particularly preferred. Heteroarylpreferably refers to pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl or thiazolyl, morepreferably pyridyl, pyrazolyl, furanyl, thiophenyl or thiazolyl, mostpreferably pyridyl.

Preferably each R¹⁰ is independently halogen, cyano, C₁-C₈haloalkyl,C₁-C₈alkoxy or C₁-C₅haloalkoxy, most preferably, fluoro, chloro, bromo,trifluoromethyl, trifluoromethoxy, cyano or methoxy.

In one embodiment of compounds of formula (I) A¹, A², A³ and A⁴ areindependently of one another C—H, C—R⁵, or nitrogen;

G¹ is oxygen or sulfur;L is a single bond or C₁-C₈alkylene;R¹ is hydrogen, C₁-C₈alkyl, C₁-C₈alkylcarbonyl-, orC₁-C₈alkoxycarbonyl-;R² is hydrogen, or C₁-C₅alkyl;R³ is C₁-C₈haloalkyl;R⁴ is aryl, aryl substituted by one to three R⁶, or R⁴ is heterocyclyl,or heterocyclyl substituted by one to three R⁶;each R⁵ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₃-C₅cycloalkyl, C₁-C₅haloalkyl, C₂-C₈alkenyl, C₂-C₅haloalkenyl,C₂-C₅alkynyl, C₂-C₅haloalkynyl, C₁-C₅alkoxy, C₁-C₅haloalkoxy,C₁-C₅alkoxycarbonyl-, or two R⁵ on adjacent carbon atoms together form a—CH═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₁-C₅haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy;Y¹ is CR⁷R⁸ or C═O;Y² and Y³ are independently CR⁷R⁸, C═O, N—R⁹, O, S, SO or SO₂;Y⁴ is CR⁷R⁸, C═O, SO or SO₂;wherein at least two adjacent ring atoms in the ring formed by Y₁, Y²,Y³ and Y⁴ are heteroatoms;each R⁷ and R⁸ is independently hydrogen, halogen, C₁-C₅alkyl, orC₁-C₅haloalkyl;each R⁹ is independently hydrogen, cyano, cyano-C₁-C₅alkyl, C₁-C₅alkyl,C₁-C₅haloalkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkyl where one carbon atomis replaced by O, S, S(O) or SO₂, C₃-C₅cycloalkyl-C₁-C₈alkyl,C₃-C₅cycloalkyl-C₁-C₈alkyl where one carbon atom in the cycloalkyl groupis replaced by O, S, S(O) or SO₂, C₃-C₅cycloalkyl-C₁-C₅haloalkyl,C₁-C₅hydroxyalkyl, C₁-C₅alkoxy-C₁-C₅alkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, phenyl-C₁-C₄alkyl,phenyl-C₁-C₄alkyl wherein the phenyl moiety is substituted by one tothree R¹⁰, or each R⁹ is independently 5-6 memberedheteroaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkyl wherein theheteroaryl moiety is substituted by one to three R¹⁰;each R¹⁰ is independently halogen, cyano, nitro, C₁-C₈alkyl,C₁-C₈haloalkyl, C₁-C₈alkoxy, or C₁-C₅haloalkoxy, or a salt of N-oxidethereof.In this embodiment each R⁹ is preferably independently hydrogen,cyano-C₁— In this embodiment each R⁹ is preferably independentlyhydrogen, cyano-C₁-C₈alkyl, C₁-C₅alkyl, C₃-C₅cycloalkyl,C₃-C₅cycloalkyl-C₁-C₅alkyl, C₁-C₅haloalkyl, C₁-C₈hydroxyalkyl,C₁-C₅alkoxyalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl, phenyl-C₁-C₄alkyl orphenyl-C₁-C₄alkyl wherein the phenyl moiety is substituted by one tothree R¹⁰, or each R⁹ is independently heteoaryl-C₁-C₄alkyl orheteroaryl-C₁-C₄alkyl wherein the heteroaryl moiety is substituted byone to three R¹⁰, even more preferably each R⁹ is independentlyhydrogen, cyano-C₁-C₈alkyl, C₁-C₈alkyl, C₃-C₈cycloalkyl, C₁-C₅haloalkyl,C₁-C₅alkoxyalkyl, C₂-C₈alkenyl, C₂-C₅alkynyl, phenyl-C₁-C₄alkyl- orphenyl-C₁-C₄alkyl wherein the phenyl moiety is substituted by one tothree R¹⁰, or each R⁹ is independently heteroaryl-C₁-C₄alkyl orheteroaryl-C₁-C₄alkyl wherein the heteroaryl moiety is substituted byone to three R¹⁰, yet even more preferably each R⁹ is independentlyhydrogen, methyl, ethyl, cyclopropyl, cyclobutyl, oxetanyl, thietanyl,trifluoroethyl, difluoroethyl, allyl, propargyl, cyanomethyl, benzyl,benzyl substituted by one to three R¹⁰, or each R⁹ is independentlypyridine-methyl- or pyridine-methyl-substituted by one to three R¹⁰. Inthis embodiment, the preferred values of Y¹, Y², Y³, Y⁴, G¹, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸ and R¹⁰ are as defined above.

A preferred embodiment provides compounds of formula (Ia.A) wherein A¹is C—R⁵, A², A³, and A⁴ are C—H, R⁴ is 3,5-dichloro-phenyl, L is a bond,and G¹, R¹, R², R³, R⁵, Y¹, Y², Y³ and Y⁴ are as defined for a compoundof formula (I); or a salt or N-oxide thereof.

A preferred embodiment provides compounds of formula (Ia.B) wherein A¹is C-Me, A², A³, and A⁴ are C—H, R⁴ is 3,5-dichloro-phenyl, L is a bond,and G¹, R¹, R², R³, Y¹, Y², Y³ and Y⁴ are as defined for a compound offormula (I); or a salt or N-oxide thereof.

A preferred embodiment provides compounds of formula (Ia.C)

whereinR² is hydrogen or C₁-C₄ alkyl;R³ is C₁-C₄ haloalkyl;R⁴ is phenyl, or phenyl substituted by one to three R⁶;R⁵ is halogen, nitro, C₁-C₄alkyl, C₃-C₄cycloalkyl, C₂-C₄alkenyl orC₁-C₄haloalkyl;A³ and A⁴ are independently C—H or N;L is a bond or methylene;R¹, R⁶, Y¹, Y², Y³, and Y⁴ are as defined for formula (I);wherein at least two adjacent ring atoms in the ring formed by Y¹, Y²,Y³ and Y⁴ are heteroatoms; or a salt or N-oxide thereof. Preferredvalues of Y¹, Y², Y³, Y⁴, A³, A⁴, R¹, R², R³, R⁴, R⁵ and R⁶ are asdefined for formula I.

A preferred embodiment provides compounds of formula (Ia.D)

whereinR⁵, Y¹, Y², Y³, Y⁴ and their preferred values are as defined for formula(I);wherein at least two adjacent ring atoms in the ring formed by Y¹, Y²,Y³ and Y⁴ are heteroatoms; or a salt or N-oxide thereof.

A further preferred embodiment provides compounds of formula (Ia.E)

wherein

A¹, A², A³, A⁴, R³, R⁴ and R⁹ and their preferred values are as definedfor a compound of formula (I); or a salt or N-oxide thereof. Certainintermediates are novel and as such form a further aspect of theinvention.

A further preferred embodiment provides compounds of formula (Ia.F)

wherein

A¹, A², A³, A⁴, R³ and R⁴ and their preferred values are as defined fora compound of formula (I); or a salt or N-oxide thereof.

Certain intermediates are novel and as such form a further aspect of theinvention. One group of novel intermediates are compounds of formula(Int-I)

wherein A¹, A², A³, A⁴, G¹, L, R¹, R², Y¹, Y², Y³ and Y⁴ are as definedfor a compound of formula (I) and X^(B) is a leaving group, for examplea halogen, such as bromo, or X^(B) is cyano, formyl, CH═N—OH or acetyl;or a salt or N-oxide thereof. The preferences for A¹, A², A³, A⁴, G¹, L,R¹, R², Y¹, Y², Y³ and Y⁴ are the same as the preferences set out forthe corresponding substituents of a compound of formula (I). Forexample, the preferences for A¹, A², A³, A⁴, G¹, L, R¹, R², Y¹, Y², Y³and Y⁴ may be the same as for formula (Ia.A), (Ia.B), (Ia.C), (Ia.D),(Ia.E) or (Ia.F).

Another group of novel intermediates are compounds of formula (Int-II)

wherein A¹, A², A³, A⁴, G¹, L, R¹, R², Y¹, Y², Y³ and Y⁴ are as definedfor a compound of formula (I); X^(C) is CH₂-halogen, wherein halogen ise.g. bromo or chloro, CH═C(R³)R⁴ or CH₂C(OH)(R³)R⁴ wherein R³ and R⁴ areas defined for a compound of formula (I); or a salt or N-oxide thereof.The preferences for A¹, A², A³, A⁴, G¹, L, R¹, R², Y¹, Y², Y³ and Y⁴ arethe same as the preferences set out for the corresponding substituentsof a compound of formula (I). For example, the preferences for A¹, A²,A³, A⁴, G¹, L, R¹, R², Y¹, Y², Y³ and Y⁴ may be the same as for formula(Ia.A), (Ia.B), (Ia.C), (Ia.D), (Ia.E) or (Ia.F).

The compounds in Table 1 to Table 2 below illustrate the compounds ofthe invention.

TABLE 1 Compound numbers R² Y² Y³ 1.01 H S S 1.02 H S(O) STable 1 provides compounds of formula (Ia) wherein R² is hydrogen, R⁵ ismethyl, Y¹ and Y⁴ are CH₂, and R², Y² and Y³ have the values listed inthe table below.

TABLE 2 Compound numbers R⁵ R⁹ 2.01 methyl ethyl- 2.02 methyl butyl-2.03 methyl but-2-yl- 2.04 methyl 3-bromo-propyl- 2.05 methyl2,2,2-trifluoro-ethyl- 2.06 methyl 3,3,3-trifluoro-propyl- 2.07 methyl2-methoxy-ethyl- 2.08 methyl 1-methoxy-prop-2-yl- 2.09 methylcyclobutyl- 2.10 methyl 2-methyl-cyclohex-1-yl- 2.11 methylphenyl-methyl- 2.12 methyl 1-phenyl-eth-1-yl- 2.13 methyl2-phenyl-eth-1-yl- 2.14 methyl (3-chloro-phenyl)-methyl- 2.15 methyl(2-fluoro-phenyl)-methyl- 2.16 methyl (4-methoxy-phenyl)-methyl- 2.17methyl (2-trifluoromethyl-phenyl)-methyl- 2.18 methyl(2-trifluoromethoxy-phenyl)-methyl- 2.19 methyl (pyrid-2-yl)-methyl-2.20 methyl (pyrid-3-yl)-methyl- 2.21 methyl(2-chloro-pyrid-5-yl)-methyl- 2.22 methyl(1-methyl-1H-imidazol-4-yl)-methyl- 2.23 methyl (furan-2-yl)-methyl-2.24 methyl 2-(thiophen-2′-yl)-eth-1-yl- 2.25 methyl2-(indol-3′-yl)-eth-1-yl- 2.26 methyl (1H-benzimidazol-2-yl)-methyl-2.27 methyl (oxetan-2-yl)-methyl- 2.28 methyl(tetrahydrofuran-2-yl)-methyl- 2.29 methyl2-([1′,3′]dioxolan-2′-yl)-eth-1-yl- 2.30 methyl2-(morpholin-4′-yl)-eth-1-yl- 2.31 methyl2-(benzo[1′,3′]dioxol-5′-yl)-eth-1-yl- 2.32 methyl(2,3-dihydro-benzo[1,4]dioxin-6-yl)-methyl- 2.33 methyl 2-chloro-phenyl-2.34 methyl 3-fluoro-phenyl- 2.35 methyl 2-methyl-phenyl- 2.36 methyl2-chloro-6-methyl-phenyl- 2.37 methyl 2-trifluoromethyl-phenyl- 2.38methyl 2,4-dimethoxy-phenyl- 2.39 methyl 3-methyl-pyrid-2-yl- 2.40methyl 1,3-dimethyl-1H-pyrazol-5-yl- 2.41 methyl 4-methyl-thiazol-2-yl-2.42 methyl 5-methyl-thiadiazol-2-yl- 2.43 methyl quinolin-2-yl- 2.44methyl quinolin-5-yl- 2.45 methyl benzothiazol-6-yl- 2.46 methyl4-methyl-benzothiazol-2-yl- 2.47 methyl thietan-3-yl- 2.48 methyl1-oxo-thietan-3-yl- 2.49 methyl 1,1-dioxo-thietan-3-yl- 2.50 methyl3-methyl-thietan-3-yl- 2.51 methyl oxetan-3yl 2.52 methyltetrahydropyran-4-yl 2.53 methyl hydrogen 2.54 methyl methyl 2.55 methylpropyl 2.56 methyl 2,2-difluoro-ethyl- 2.57 methyl 2-fluoro-ethyl-Table 2 provides compounds of formula (Ib) wherein G¹ is oxygen, and R⁵and R⁹ have the values listed in the table below.

Compounds of formula I include at least one chiral centre and may existas compounds of formula I* or compounds of formula I**. Compounds I* andI** are enantiomers if there is no other chiral center or epimersotherwise.

Generally compounds of formula I** are more biologically active thancompounds of formula I*. The invention includes mixtures of compounds I*and I** in any ratio e.g. in a molar ratio of 1:99 to 99:1, e.g. 10:1 to1:10, e.g. a substantially 50:50 molar ratio. In an enantiomerically (orepimerically) enriched mixture of formula I**, the molar proportion ofcompound I** compared to the total amount of both enantiomers is forexample greater than 50%, e.g. at least 55, 60, 65, 70, 75, 80, 85, 90,95, 96, 97, 98, or at least 99%. Likewise, in enantiomerically (orepimerically) enriched mixture of formula I*, the molar proportion ofthe compound of formula I* compared to the total amount of bothenantiomers (or epimerically) is for example greater than 50%, e.g. atleast 55, 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or at least 99%.Enantiomerically (or epimerically) enriched mixtures of formula I** arepreferred.

The compounds of the invention may be made by a variety of methods asshown in Schemes 1 and 2.

1) Compounds of formula (I) wherein G¹ is oxygen, can be prepared byreacting a compound of formula (II) wherein G¹ is oxygen and R is OH,C₁-C₆alkoxy or Cl, F or Br, with an amine of formula (III) as shown inScheme 1. When R is OH such reactions are usually carried out in thepresence of a coupling reagent, such as N,N′-dicyclohexylcarbo-diimide(“DCC”), 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride(“EDC”) or bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”), inthe presence of a base, and optionally in the presence of a nucleophiliccatalyst, such as hydroxybenzotriazole (“HOBT”). When R is Cl, suchreactions are usually carried out in the presence of a base, andoptionally in the presence of a nucleophilic catalyst. Alternatively, itis possible to conduct the reaction in a biphasic system comprising anorganic solvent, preferably ethyl acetate, and an aqueous solvent,preferably a solution of sodium hydrogen carbonate. When R isC₁-C₆alkoxy it is sometimes possible to convert the ester directly tothe amide by heating the ester and amine together in a thermal process.Suitable bases include pyridine, triethylamine,4-(dimethylamino)-pyridine (“DMAP”) or diisopropylethylamine (Hunig'sbase). Preferred solvents are N,N-dimethylacetamide, tetrahydrofuran,dioxane, 1,2-dimethoxyethane, ethyl acetate and toluene. The reaction iscarried out at a temperature of from 0° C. to 100° C., preferably from15° C. to 30° C., in particular at ambient temperature.

Amines of formula (III) are either known in the literature or can beprepared using methods known to a person skilled in the art. Some ofthese methods are described in the preparation Examples.

2) Acid halides of formula (II), wherein G¹ is oxygen and R is Cl, F orBr, may be made from carboxylic acids of formula (II), wherein G¹ isoxygen and R is OH, under standard conditions, as described for examplein WO09080250.

3) Carboxylic acids of formula (II), wherein G¹ is oxygen and R is OH,may be formed from esters of formula (II), wherein G¹ is oxygen and R isC₁-C₆alkoxy as described for example in WO09080250.

4) Compounds of formula (I) wherein G¹ is oxygen, can be prepared byreacting a compound of formula (IV) wherein X^(B) is a leaving group,for example a halogen, such as bromo, with carbon monoxide and an amineof formula (III), in the presence of a catalyst, such as palladium(II)acetate or bis(triphenylphosphine)palladium(II) dichloride, optionallyin the presence of a ligand, such as triphenylphosphine, and a base,such as sodium carbonate, pyridine, triethylamine,4-(dimethylamino)-pyridine (“DMAP”) or diisopropylethylamine (Hunig'sbase), in a solvent, such as water, N,N-dimethylformamide ortetrahydrofuran. The reaction is carried out at a temperature of from50° C. to 200° C., preferably from 100° C. to 150° C. The reaction iscarried out at a pressure of from 50 to 200 bar, preferably from 100 to150 bar.

5) Compounds of formula (IV) wherein X^(B) is a leaving group, forexample a halogen, such as bromo, can be made by a various of methods,for example as described in WO09080250.

6) Compounds of formula (I), wherein G¹ is sulfur, may be made bytreatment of a compound of formula (II), wherein G¹ is oxygen and R isOH, C₁-C₆alkoxy or Cl, F or Br, with a thio-transfer reagent such asLawesson's reagent or phosphorus pentasulfide prior to elaborating tocompounds of formula (I), as described under 1).

7) Alternatively, compounds of formula (I) wherein G¹ is oxygen, can beprepared by various methods from an intermediate of formula (V) as shownin Scheme 2 wherein G¹ is oxygen and X^(B) is a leaving group, forexample a halogen, such as bromo, or X^(B) is cyano, formyl or acetylaccording to similar methods to those described in WO09080250. Anintermediate of formula (V) can be prepared for example from anintermediate of formula (VI) as described in the same reference.

8) Alternatively, compounds of formula (I) wherein G¹ is oxygen, can beprepared by various methods from an intermediate of formula (VII) asshown in Scheme 3 wherein G¹ is oxygen and X^(C) is CH═C(R³)R⁴, orCH₂C(OH)(R³)R⁴ wherein R³ and R⁴ are as defined for a compound offormula (I) according to similar methods to those described inWO09080250.

9) Compounds of formula (VII) wherein G¹ is oxygen and X^(C) isCH═C(R³)R⁴, or CH₂C(OH)(R³)R⁴ can be prepared from a compound of formula(Va) wherein G¹ is oxygen or from a compound of formula (VII) wherein G¹is oxygen and X^(C) is CH₂-halogen using similar methods to thosedescribed in WO09080250.

10) Compounds of formula (VII) wherein G¹ is oxygen and X^(C) isCH₂-halogen, such as bromo or chloro, can be prepared by reacting amethyl ketone of formula (Va) wherein G¹ is oxygen, with a halogenatingagent, such as bromine or chlorine, in a solvent, such as acetic acid,at a temperature of from 0° C. to 50° C., preferably from ambienttemperature to 40° C.

11) Compounds of formula (III) are either known compounds or can beprepared by known methods to the person skilled in the art. Examples ofsuch methods can be found in the Examples below.

The compounds of formula (I) can be used to combat and controlinfestations of insect pests such as Lepidoptera, Diptera, Hemiptera,Thysanoptera, Orthoptera, Dictyoptera, Coleoptera, Siphonaptera,Hymenoptera and Isoptera and also other invertebrate pests, for example,acarine, nematode and mollusc pests. Insects, acarines, nematodes andmolluscs are hereinafter collectively referred to as pests. The pestswhich may be combated and controlled by the use of the inventioncompounds include those pests associated with agriculture (which termincludes the growing of crops for food and fiber products), horticultureand animal husbandry, companion animals, forestry and the storage ofproducts of vegetable origin (such as fruit, grain and timber); thosepests associated with the damage of man-made structures and thetransmission of diseases of man and animals; and also nuisance pests(such as flies).

The compounds of the invention may be used for example on turf,ornamentals, such as flowers, shrubs, broad-leaved trees or evergreens,for example conifers, as well as for tree injection, pest management andthe like.

Examples of pest species which may be controlled by the compounds offormula (I) include: Myzus persicae (aphid), Aphis gossypii (aphid),Aphisfabae (aphid), Lygus spp. (capsids), Dysdercus spp. (capsids),Nilaparvata lugens (planthopper), Nephotettixc incticeps (leafhopper),Nezara spp. (stinkbugs), Euschistus spp. (stinkbugs), Leptocorisa spp.(stinkbugs), Frankliniella occidentalis (thrip), Thrips spp. (thrips),Leptinotarsa decemlineata (Colorado potato beetle), Anthonomus grandis(boll weevil), Aonidiella spp. (scale insects), Trialeurodes spp. (whiteflies), Bemisia tabaci (white fly), Ostrinia nubilalis (European cornborer), Spodoptera littoralis (cotton leafworm), Heliothis virescens(tobacco budworm), Helicoverpa armigera (cotton bollworm), Helicoverpazea (cotton bollworm), Sylepta derogata (cotton leaf roller), Pierisbrassicae (white butterfly), Plutella xylostella (diamond back moth),Agrotis spp. (cutworms), Chilo suppressalis (rice stem borer), Locustamigratoria (locust), Chortiocetes terminifera (locust), Diabrotica spp.(rootworms), Panonychus ulmi (European red mite), Panonychus citri(citrus red mite), Tetranychus urticae (two-spotted spider mite),Tetranychus cinnabarinus (carmine spider mite), Phyllocoptruta oleivora(citrus rust mite), Polyphagotarsonemus latus (broad mite), Brevipalpusspp. (flat mites), Boophilus microplus (cattle tick), Dermacentorvariabilis (American dog tick), Ctenocephalidesfelis (cat flea),Liriomyza spp. (leafminer), Musca domestica (housefly), Aedes aegypti(mosquito), Anopheles spp. (mosquitoes), Culex spp. (mosquitoes),Lucillia spp. (blowflies), Blattella germanica (cockroach), Periplanetaamericana (cockroach), Blatta orientalis (cockroach), termites of theMastotermitidae (for example Mastotermes spp.), the Kalotermitidae (forexample Neotermes spp.), the Rhinotermitidae (for example Coptotermesformosanus, Reticulitermes flavipes, R. speratu, R. virginicus, R.hesperus, and R. santonensis) and the Termitidae (for exampleGlobitermes sulfureus), Solenopsis geminata (fire ant), Monomoriumpharaonis (pharaoh's ant), Damalinia spp. and Linognathus spp. (bitingand sucking lice), Meloidogyne spp. (root knot nematodes), Globoderaspp. and Heterodera spp. (cyst nematodes), Pratylenchus spp. (lesionnematodes), Rhodopholus spp. (banana burrowing nematodes), Tylenchulusspp (citrus nematodes), Haemonchus contortus (barber pole worm),Caenorhabditis elegans (vinegar eelworm), Trichostrongylus spp. (gastrointestinal nematodes) and Deroceras reticulatum (slug).

The invention therefore provides a method of combating and/orcontrolling an animal pest, e.g. an invertebrate animal pest, whichcomprises applying to the pest, to a locus of the pest, or to a plantsusceptible to attack by the pest a pesticidally effective amount of acompound of formula (I). In particular, the invention provides a methodof combating and/or controlling insects, acarines, nematodes or molluscswhich comprises applying an insecticidally, acaricidally, nematicidallyor molluscicidally effective amount of a compound of formula (I), or acomposition containing a compound of formula (I), to a pest, a locus ofpest, preferably a plant, or to a plant susceptible to attack by a pest,The compounds of formula (I) are preferably used against insects,acarines or nematodes.

The term “plant” as used herein includes seedlings, bushes and trees.

Crops are to be understood as also including those crops which have beenrendered tolerant to herbicides or classes of herbicides (e.g. ALS-,GS-, EPSPS-, PPO- and HPPD-inhibitors) by conventional methods ofbreeding or by genetic engineering. An example of a crop that has beenrendered tolerant to imidazolinones, e.g. imazamox, by conventionalmethods of breeding is Clearfield® summer rape (canola). Examples ofcrops that have been rendered tolerant to herbicides by geneticengineering methods include e.g. glyphosate- and glufosinate-resistantmaize varieties commercially available under the trade namesRoundupReady® and LibertyLink®.

Crops are also to be understood as being those which have been renderedresistant to harmful insects by genetic engineering methods, for exampleBt maize (resistant to European corn borer), Bt cotton (resistant tocotton boll weevil) and also Bt potatoes (resistant to Colorado beetle).Examples of Bt maize are the Bt 176 maize hybrids of NK® (SyngentaSeeds). Examples of transgenic plants comprising one or more genes thatcode for an insecticidal resistance and express one or more toxins areKnockOut® (maize), Yield Gard® (maize), NuCOTIN33B® (cotton), Bollgard®(cotton), NewLeaf® (potatoes), NatureGard® and Protexcta@.

Plant crops or seed material thereof can be both resistant to herbicidesand, at the same time, resistant to insect feeding (“stacked” transgenicevents). For example, seed can have the ability to express aninsecticidal Cry3 protein while at the same time being tolerant toglyphosate.

Crops are also to be understood as being those which are obtained byconventional methods of breeding or genetic engineering and containso-called output traits (e.g. improved storage stability, highernutritional value and improved flavor).

In order to apply a compound of formula (I) as an insecticide,acaricide, nematicide or molluscicide to a pest, a locus of pest, or toa plant susceptible to attack by a pest, a compound of formula (I) isusually formulated into a composition which includes, in addition to thecompound of formula (I), a suitable inert diluent or carrier and,optionally, a surface active agent (SFA). SFAs are chemicals which areable to modify the properties of an interface (for example,liquid/solid, liquid/air or liquid/liquid interfaces) by lowering theinterfacial tension and thereby leading to changes in other properties(for example dispersion, emulsification and wetting). It is preferredthat all compositions (both solid and liquid formulations) comprise, byweight, 0.0001 to 95%, more preferably 1 to 85%, for example 5 to 60%,of a compound of formula (I). The composition is generally used for thecontrol of pests such that a compound of formula (I) is applied at arate of from 0.1 g to 10 kg per hectare, preferably from 1 g to 6 kg perhectare, more preferably from 1 g to 1 kg per hectare.

When used in a seed dressing, a compound of formula (I) is used at arate of 0.0001 g to 10 g (for example 0.001 g or 0.05 g), preferably0.005 g to 10 g, more preferably 0.005 g to 4 g, per kilogram of seed.

In another aspect the present invention provides a compositioncomprising a pesticidally effective amount of a compound of formula (I),in particular an insecticidal, acaricidal, nematicidal or molluscicidalcomposition comprising an insecticidally, acaricidally, nematicidally ormolluscicidally effective amount of a compound of formula (I) and asuitable carrier or diluent therefor. The composition is preferably aninsecticidal, acaricidal, nematicidal or molluscicidal composition.

The compositions can be chosen from a number of formulation types,including dustable powders (DP), soluble powders (SP), water solublegranules (SG), water dispersible granules (WG), wettable powders (WP),granules (GR) (slow or fast release), soluble concentrates (SL), oilmiscible liquids (OL), ultra low volume liquids (UL), emulsifiableconcentrates (EC), dispersible concentrates (DC), emulsions (both oil inwater (EW) and water in oil (EO)), micro-emulsions (ME), suspensionconcentrates (SC), aerosols, fogging/smoke formulations, capsulesuspensions (CS) and seed treatment formulations. The formulation typechosen in any instance will depend upon the particular purpose envisagedand the physical, chemical and biological properties of the compound offormula (I).

Dustable powders (DP) may be prepared by mixing a compound of formula(I) with one or more solid diluents (for example natural clays, kaolin,pyrophyllite, bentonite, alumina, montmorillonite, kieselguhr, chalk,diatomaceous earths, calcium phosphates, calcium and magnesiumcarbonates, sulfur, lime, flours, talc and other organic and inorganicsolid carriers) and mechanically grinding the mixture to a fine powder.

Soluble powders (SP) may be prepared by mixing a compound of formula (I)with one or more water-soluble inorganic salts (such as sodiumbicarbonate, sodium carbonate or magnesium sulfate) or one or morewater-soluble organic solids (such as a polysaccharide) and, optionally,one or more wetting agents, one or more dispersing agents or a mixtureof said agents to improve water dispersibility/solubility. The mixtureis then ground to a fine powder. Similar compositions may also begranulated to form water soluble granules (SG).

Wettable powders (WP) may be prepared by mixing a compound of formula(I) with one or more solid diluents or carriers, one or more wettingagents and, preferably, one or more dispersing agents and, optionally,one or more suspending agents to facilitate the dispersion in liquids.The mixture is then ground to a fine powder. Similar compositions mayalso be granulated to form water dispersible granules (WG).

Granules (GR) may be formed either by granulating a mixture of acompound of formula (I) and one or more powdered solid diluents orcarriers, or from pre-formed blank granules by absorbing a compound offormula (I) (or a solution thereof, in a suitable agent) in a porousgranular material (such as pumice, attapulgite clays, fuller's earth,kieselguhr, diatomaceous earths or ground corn cobs) or by adsorbing acompound of formula (I) (or a solution thereof, in a suitable agent) onto a hard core material (such as sands, silicates, mineral carbonates,sulfates or phosphates) and drying if necessary. Agents which arecommonly used to aid absorption or adsorption include solvents (such asaliphatic and aromatic petroleum solvents, alcohols, ethers, ketones andesters) and sticking agents (such as polyvinyl acetates, polyvinylalcohols, dextrins, sugars and vegetable oils). One or more otheradditives may also be included in granules (for example an emulsifyingagent, wetting agent or dispersing agent).

Dispersible Concentrates (DC) may be prepared by dissolving a compoundof formula (I) in water or an organic solvent, such as a ketone, alcoholor glycol ether. These solutions may contain a surface active agent (forexample to improve water dilution or prevent crystallization in a spraytank).

Emulsifiable concentrates (EC) or oil-in-water emulsions (EW) may beprepared by dissolving a compound of formula (I) in an organic solvent(optionally containing one or more wetting agents, one or moreemulsifying agents or a mixture of said agents). Suitable organicsolvents for use in ECs include aromatic hydrocarbons (such asalkylbenzenes or alkylnaphthalenes, exemplified by SOLVESSO 100,SOLVESSO 150 and SOLVESSO 200; SOLVESSO is a Registered Trade Mark),ketones (such as cyclohexanone or methylcyclohexanone) and alcohols(such as benzyl alcohol, furfuryl alcohol or butanol),N-alkylpyrrolidones (such as N-methylpyrrolidone or N-octylpyrrolidone),dimethyl amides of fatty acids (such as C₈-C₁₀ fatty acid dimethylamide)and chlorinated hydrocarbons. An EC product may spontaneously emulsifyon addition to water, to produce an emulsion with sufficient stabilityto allow spray application through appropriate equipment. Preparation ofan EW involves obtaining a compound of formula (I) either as a liquid(if it is not a liquid at room temperature, it may be melted at areasonable temperature, typically below 70° C.) or in solution (bydissolving it in an appropriate solvent) and then emulsifiying theresultant liquid or solution into water containing one or more SFAs,under high shear, to produce an emulsion. Suitable solvents for use inEWs include vegetable oils, chlorinated hydrocarbons (such aschlorobenzenes), aromatic solvents (such as alkylbenzenes oralkylnaphthalenes) and other appropriate organic solvents which have alow solubility in water.

Microemulsions (ME) may be prepared by mixing water with a blend of oneor more solvents with one or more SFAs, to produce spontaneously athermodynamically stable isotropic liquid formulation. A compound offormula (I) is present initially in either the water or the solvent/SFAblend. Suitable solvents for use in MEs include those hereinbeforedescribed for use in ECs or in EWs. An ME may be either an oil-in-wateror a water-in-oil system (which system is present may be determined byconductivity measurements) and may be suitable for mixing water-solubleand oil-soluble pesticides in the same formulation. An ME is suitablefor dilution into water, either remaining as a microemulsion or forminga conventional oil-in-water emulsion.

Suspension concentrates (SC) may comprise aqueous or non-aqueoussuspensions of finely divided insoluble solid particles of a compound offormula (I). SCs may be prepared by ball or bead milling the solidcompound of formula (I) in a suitable medium, optionally with one ormore dispersing agents, to produce a fine particle suspension of thecompound.

One or more wetting agents may be included in the composition and asuspending agent may be included to reduce the rate at which theparticles settle. Alternatively, a compound of formula (I) may be drymilled and added to water, containing agents hereinbefore described, toproduce the desired end product.

Aerosol formulations comprise a compound of formula (I) and a suitablepropellant (for example n-butane). A compound of formula (I) may also bedissolved or dispersed in a suitable medium (for example water or awater miscible liquid, such as n-propanol) to provide compositions foruse in non-pressurized, hand-actuated spray pumps.

A compound of formula (I) may be mixed in the dry state with apyrotechnic mixture to form a composition suitable for generating, in anenclosed space, a smoke containing the compound.

Capsule suspensions (CS) may be prepared in a manner similar to thepreparation of EW formulations but with an additional polymerizationstage such that an aqueous dispersion of oil droplets is obtained, inwhich each oil droplet is encapsulated by a polymeric shell and containsa compound of formula (I) and, optionally, a carrier or diluenttherefor. The polymeric shell may be produced by either an interfacialpolycondensation reaction or by a coacervation procedure. Thecompositions may provide for controlled release of the compound offormula (I) and they may be used for seed treatment. A compound offormula (I) may also be formulated in a biodegradable polymeric matrixto provide a slow, controlled release of the compound.

A composition may include one or more additives to improve thebiological performance of the composition (for example by improvingwetting, retention or distribution on surfaces; resistance to rain ontreated surfaces; or uptake or mobility of a compound of formula (I)).Such additives include surface active agents, spray additives based onoils, for example certain mineral oils or natural plant oils (such assoy bean and rape seed oil), and blends of these with otherbio-enhancing adjuvants (ingredients which may aid or modify the actionof a compound of formula (I)).

A compound of formula (I) may also be formulated for use as a seedtreatment, for example as a powder composition, including a powder fordry seed treatment (DS), a water soluble powder (SS) or a waterdispersible powder for slurry treatment (WS), or as a liquidcomposition, including a flowable concentrate (FS), a solution (LS) or acapsule suspension (CS). The preparations of DS, SS, WS, FS and LScompositions are very similar to those of, respectively, DP, SP, WP, SCand DC compositions described above. Compositions for treating seed mayinclude an agent for assisting the adhesion of the composition to theseed (for example a mineral oil or a film-forming barrier).

Wetting agents, dispersing agents and emulsifying agents may be surfaceSFAs of the cationic, anionic, amphoteric or non-ionic type.

Suitable SFAs of the cationic type include quaternary ammonium compounds(for example cetyltrimethyl ammonium bromide), imidazolines and aminesalts.

Suitable anionic SFAs include alkali metals salts of fatty acids, saltsof aliphatic monoesters of sulfuric acid (for example sodium laurylsulfate), salts of sulfonated aromatic compounds (for example sodiumdodecylbenzenesulfonate, calcium dodecylbenzenesulfonate,butylnaphthalene sulfonate and mixtures of sodium di-isopropyl- andtri-isopropyl-naphthalene sulfonates), ether sulfates, alcohol ethersulfates (for example sodium laureth-3-sulfate), ether carboxylates (forexample sodium laureth-3-carboxylate), phosphate esters (products fromthe reaction between one or more fatty alcohols and phosphoric acid(predominately mono-esters) or phosphorus pentoxide (predominatelydi-esters), for example the reaction between lauryl alcohol andtetraphosphoric acid; additionally these products may be ethoxylated),sulfosuccinamates, paraffin or olefine sulfonates, taurates andlignosulfonates.

Suitable SFAs of the amphoteric type include betaines, propionates andglycinates.

Suitable SFAs of the non-ionic type include condensation products ofalkylene oxides, such as ethylene oxide, propylene oxide, butylene oxideor mixtures thereof, with fatty alcohols (such as oleyl alcohol or cetylalcohol) or with alkylphenols (such as octylphenol, nonylphenol oroctylcresol); partial esters derived from long chain fatty acids orhexitol anhydrides; condensation products of said partial esters withethylene oxide; block polymers (comprising ethylene oxide and propyleneoxide); alkanolamides; simple esters (for example fatty acidpolyethylene glycol esters); amine oxides (for example lauryl dimethylamine oxide); and lecithins.

Suitable suspending agents include hydrophilic colloids (such aspolysaccharides, polyvinylpyrrolidone or sodium carboxymethylcellulose)and swelling clays (such as bentonite or attapulgite).

A compound of formula (I) may be applied by any of the known means ofapplying pesticidal compounds. For example, it may be applied,formulated or unformulated, to the pests or to a locus of the pests(such as a habitat of the pests, or a growing plant liable toinfestation by the pests) or to any part of the plant, including thefoliage, stems, branches or roots, to the seed before it is planted orto other media in which plants are growing or are to be planted (such assoil surrounding the roots, the soil generally, paddy water orhydroponic culture systems), directly or it may be sprayed on, dustedon, applied by dipping, applied as a cream or paste formulation, appliedas a vapor or applied through distribution or incorporation of acomposition (such as a granular composition or a composition packed in awater-soluble bag) in soil or an aqueous environment.

A compound of formula (I) may also be injected into plants or sprayedonto vegetation using electrodynamic spraying techniques or other lowvolume methods, or applied by land or aerial irrigation systems.

Compositions for use as aqueous preparations (aqueous solutions ordispersions) are generally supplied in the form of a concentratecontaining a high proportion of the active ingredient, the concentratebeing added to water before use. These concentrates, which may includeDCs, SCs, ECs, EWs, MEs, SGs, SPs, WPs, WGs and CSs, are often requiredto withstand storage for prolonged periods and, after such storage, tobe capable of addition to water to form aqueous preparations whichremain homogeneous for a sufficient time to enable them to be applied byconventional spray equipment. Such aqueous preparations may containvarying amounts of a compound of formula (I) (for example 0.0001 to 10%,by weight) depending upon the purpose for which they are to be used.

A compound of formula (I) may be used in mixtures with fertilizers (forexample nitrogen-, potassium- or phosphorus-containing fertilizers).Suitable formulation types include granules of fertilizer. The mixturespreferably contain up to 25% by weight of the compound of formula (I).

The invention therefore also provides a fertilizer compositioncomprising a fertilizer and a compound of formula (I).

The compositions of this invention may contain other compounds havingbiological activity, for example micronutrients or compounds havingfungicidal activity or which possess plant growth regulating,herbicidal, insecticidal, nematicidal or acaricidal activity.

The compound of formula (I) may be the sole active ingredient of thecomposition or it may be admixed with one or more additional activeingredients such as a pesticide, e.g. a insecticide, fungicide orherbicide, or a synergist or plant growth regulator where appropriate.An additional active ingredient may provide a composition having abroader spectrum of activity or increased persistence at a locus;synergize the activity or complement the activity (for example byincreasing the speed of effect or overcoming repellency) of the compoundof formula (I); or help to overcome or prevent the development ofresistance to individual components. The particular additional activeingredient will depend upon the intended utility of the composition.Examples of suitable pesticides include the following:

a) Pyrethroids, such as permethrin, cypermethrin, fenvalerate,esfenvalerate, deltamethrin, cyhalothrin (in particularlambda-cyhalothrin and gamma cyhalothrin), bifenthrin, fenpropathrin,cyfluthrin, tefluthrin, fish safe pyrethroids (for example ethofenprox),natural pyrethrin, tetramethrin, S-bioallethrin, fenfluthrin,prallethrin or5-benzyl-3-furylmethyl-(E)-(1R,3S)-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate;b) Organophosphates, such as profenofos, sulprofos, acephate, methylparathion, azinphos-methyl, demeton-s-methyl, heptenophos, thiometon,fenamiphos, monocrotophos, profenofos, triazophos, methamidophos,dimethoate, phosphamidon, malathion, chlorpyrifos, phosalone, terbufos,fensulfothion, fonofos, phorate, phoxim, pirimiphos-methyl,pirimiphos-ethyl, fenitrothion, fosthiazate or diazinon;c) Carbamates (including aryl carbamates), such as pirimicarb,triazamate, cloethocarb, carbofuran, furathiocarb, ethiofencarb,aldicarb, thiofurox, carbosulfan, bendiocarb, fenobucarb, propoxur,methomyl or oxamyl;d) Benzoyl ureas, such as diflubenzuron, triflumuron, hexaflumuron,flufenoxuron, lufeneron or chlorfluazuron;e) Organic tin compounds, such as cyhexatin, fenbutatin oxide orazocyclotin;f) Pyrazoles, such as tebufenpyrad and fenpyroximate;g) Macrolides, such as avermectins or milbemycins, for exampleabamectin, emamectin benzoate, ivermectin, milbemycin, spinosad,azadirachtin or spinetoram;h) Hormones or pheromones;i) Organochlorine compounds, such as endosulfan (in particularalpha-endosulfan), benzene hexachloride, DDT, chlordane or dieldrin;j) Amidines, such as chlordimeform or amitraz;k) Fumigant agents, such as chloropicrin, dichloropropane, methylbromide or metam;l) Neonicotinoid compounds, such as imidacloprid, thiacloprid,acetamiprid, nitenpyram, dinotefuran, thiamethoxam, clothianidin,nithiazine or flonicamid;m) Diacylhydrazines, such as tebufenozide, chromafenozide ormethoxyfenozide;n) Diphenyl ethers, such as diofenolan or pyriproxifen;

o) Indoxacarb; p) Chlorfenapyr; q) Pymetrozine;

r) Spirotetramat, spirodiclofen or spiromesifen;s) Diamides, such as flubendiamide, chlorantraniliprole (Rynaxypyr®) orcyantraniliprole;

t) Sulfoxaflor; or u) Metaflumizone; v) Fipronil and Ethiprole; w)Pyrifluqinazon;

x) buprofezin; ory)4-[(6-Chloro-pyridin-3-ylmethyl)-(2,2-difluoro-ethyl)-amino]-5H-furan-2-one(DE 102006015467) In addition to the major chemical classes of pesticidelisted above, other pesticides having particular targets may be employedin the composition, if appropriate for the intended utility of thecomposition. For instance, selective insecticides for particular crops,for example stemborer specific insecticides (such as cartap) or hopperspecific insecticides (such as buprofezin) for use in rice may beemployed. Alternatively insecticides or acaricides specific forparticular insect species/stages may also be included in thecompositions (for example acaricidal ovo-larvicides, such asclofentezine, flubenzimine, hexythiazox or tetradifon; acaricidalmotilicides, such as dicofol or propargite; acaricides, such asbromopropylate or chlorobenzilate; or growth regulators, such ashydramethylnon, cyromazine, methoprene, chlorfluazuron ordiflubenzuron).

Examples of fungicidal compounds which may be included in thecomposition of the invention are(E)-N-methyl-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-iminoacetamide(SSF-129),4-bromo-2-cyano-N,N-dimethyl-6-trifluoromethyl-benzimidazole-1-sulfonamide,α-[N-(3-chloro-2,6-xylyl)-2-methoxyacetamido]-γ-butyrolactone,4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide (IKF-916,cyamidazosulfamid),3-5-dichloro-N-(3-chloro-1-ethyl-1-methyl-2-oxopropyl)-4-methylbenzamide(RH-7281, zoxamide),N-allyl-4,5-dimethyl-2-trimethylsilylthiophene-3-carboxamide (MON65500),N-(1-cyano-1,2-dimethylpropyl)-2-(2,4-dichlorophenoxy)propionamide(AC382042), N-(2-methoxy-5-pyridyl)-cyclopropane carboxamide,acibenzolar (CGA245704) (e.g. acibenzolar-S-methyl), alanycarb,aldimorph, anilazine, azaconazole, azoxystrobin, benalaxyl, benomyl,benthiavalicarb, biloxazol, bitertanol, bixafen, blasticidin S,boscalid, bromuconazole, bupirimate, captafol, captan, carbendazim,carbendazim chlorhydrate, carboxin, carpropamid, carvone, CGA41396,CGA41397, chinomethionate, chlorothalonil, chlorozolinate, clozylacon,copper containing compounds such as copper oxychloride, copperoxyquinolate, copper sulfate, copper tallate and Bordeaux mixture,cyclufenamid, cymoxanil, cyproconazole, cyprodinil, debacarb,di-2-pyridyl disulfide 1,1′-dioxide, dichlofluanid, diclomezine,dicloran, diethofencarb, difenoconazole, difenzoquat, diflumetorim,O,O-di-iso-propyl-S-benzyl thiophosphate, dimefluazole, dimetconazole,dimethomorph, dimethirimol, diniconazole, dinocap, dithianon, dodecyldimethyl ammonium chloride, dodemorph, dodine, doguadine, edifenphos,epoxiconazole, ethirimol,ethyl-(Z)—N-benzyl-N-([methyl(methyl-thioethylideneaminooxycarbonyl)amino]thio)-(3-alaninate, etridiazole, famoxadone, fenamidone(RPA407213), fenarimol, fenbuconazole, fenfuram, fenhexamid (KBR2738),fenpiclonil, fenpropidin, fenpropimorph, fentin acetate, fentinhydroxide, ferbam, ferimzone, fluazinam, fludioxonil, flumetover,fluopyram, fluoxastrobin, fluoroimide, fluquinconazole, flusilazole,flutolanil, flutriafol, fluxapyroxad, folpet, fuberidazole, furalaxyl,furametpyr, guazatine, hexaconazole, hydroxyisoxazole, hymexazole,imazalil, imibenconazole, iminoctadine, iminoctadine triacetate,ipconazole, iprobenfos, iprodione, iprovalicarb (SZX0722), isopropanylbutyl carbamate, isoprothiolane, isopyrazam, kasugamycin,kresoxim-methyl, LY186054, LY211795, LY248908, mancozeb, mandipropamid,maneb, mefenoxam, metalaxyl, mepanipyrim, mepronil, metalaxyl,metconazole, metiram, metiram-zinc, metominostrobin, myclobutanil,neoasozin, nickel dimethyldithiocarbamate, nitrothal-isopropyl,nuarimol, ofurace, organomercury compounds, oxadixyl, oxasulfuron,oxolinic acid, oxpoconazole, oxycarboxin, pefurazoate, penconazole,pencycuron, penflufen, penthiopyrad, phenazin oxide, phosetyl-Al,phosphorus acids, phthalide, picoxystrobin (ZA1963), polyoxinD, polyram,probenazole, prochloraz, procymidone, propamocarb, propiconazole,propineb, propionic acid, prothioconazole, pyrazophos, pyrifenox,pyrimethanil, pyraclostrobin, pyroquilon, pyroxyfur, pyrrolnitrin,quaternary ammonium compounds, quinomethionate, quinoxyfen, quintozene,sedaxane, sipconazole (F-155), sodium pentachlorophenate, spiroxamine,streptomycin, sulfur, tebuconazole, tecloftalam, tecnazene,tetraconazole, thiabendazole, thifluzamid,2-(thiocyanomethylthio)benzothiazole, thiophanate-methyl, thiram,timibenconazole, tolclofos-methyl, tolylfluanid, triadimefon,triadimenol, triazbutil, triazoxide, tricyclazole, tridemorph,trifloxystrobin (CGA279202), triforine, triflumizole, triticonazole,validamycin A, vapam, vinclozolin, zineb and ziram,1,3-Dimethyl-1H-pyrazole-4-carboxylic acid(4′-methylsulfanyl-biphenyl-2-yl)-amide,1,3-Dimethyl-1H-pyrazole-4-carboxylic acid(2-dichloromethylene-3-ethyl-1-methyl-indan-4-yl)-amide, and1,3-Dimethyl-4H-pyrazole-4-carboxylic acid[2-(2,4-dichloro-phenyl)-2-methoxy-1-methyl-ethyl]-amide.

The compounds of formula (I) may be mixed with soil, peat or otherrooting media for the protection of plants against seed-borne,soil-borne or foliar fungal diseases.

Examples of suitable synergists for use in the compositions includepiperonyl butoxide, sesamex, safroxan and dodecyl imidazole.

Suitable herbicides and plant-growth regulators for inclusion in thecompositions will depend upon the intended target and the effectrequired.

An example of a rice selective herbicide which may be included ispropanil. An example of a plant growth regulator for use in cotton isPIX™.

Some mixtures may comprise active ingredients which have significantlydifferent physical, chemical or biological properties such that they donot easily lend themselves to the same conventional formulation type. Inthese circumstances other formulation types may be prepared. Forexample, where one active ingredient is a water insoluble solid and theother a water insoluble liquid, it may nevertheless be possible todisperse each active ingredient in the same continuous aqueous phase bydispersing the solid active ingredient as a suspension (using apreparation analogous to that of an SC) but dispersing the liquid activeingredient as an emulsion (using a preparation analogous to that of anEW). The resultant composition is a suspoemulsion (SE) formulation.

The compounds of the invention are also useful in the field of animalhealth, e.g. they may be used against parasitic invertebrate pests, morepreferably against parasitic invertebrate pests in or on an animal.Examples of pests include nematodes, trematodes, cestodes, flies, mites,tricks, lice, fleas, true bugs and maggots. The animal may be anon-human animal, e.g. an animal associated with agriculture, e.g. acow, a pig, a sheep, a goat, a horse, or a donkey, or a companionanimal, e.g. a dog or a cat.

In a further aspect the invention provides a compound of the inventionfor use in a method of therapeutic treatment.

In a further aspect the invention relates to a method of controllingparasitic invertebrate pests in or on an animal comprising administeringa pesticidally effective amount of a compound of the invention. Theadministration may be for example oral administration, parenteraladministration or external administration, e.g. to the surface of theanimal body. In a further aspect the invention relates to a compound ofthe invention for controlling parasitic invertebrate pests in or on ananimal. In a further aspect the invention relates to use of a compoundof the invention in the manufacture of a medicament for controllingparasitic invertebrate pests in or on an animal

In a further aspect, the invention relates to a method of controllingparasitic invertebrate pests comprising administering a pesticidallyeffective amount of a compound of the invention to the environment inwhich an animal resides.

In a further aspect the invention relates to a method of protecting ananimal from a parasitic invertebrate pest comprising administering tothe animal a pesticidally effective amount of a compound of theinvention. In a further aspect the invention relates to a compound ofthe invention for use in protecting an animal from a parasiticinvertebrate pest. In a further aspect the invention relates to use of acompound of the invention in the manufacture of a medicament forprotecting an animal from a parasitic invertebrate pest.

In a further aspect the invention provides a method of treating ananimal suffering from a parasitic invertebrate pest comprisingadministering to the animal a pesticidally effective amount of acompound of the invention. In a further aspect the invention relates toa compound of the invention for use in treating an animal suffering froma parasitic invertebrate pest. In a further aspect the invention relatesto use of a compound of the invention in the manufacture of a medicamentfor treating an animal suffering from a parasitic invertebrate pest.

In a further aspect, the invention provides a pharmaceutical compositioncomprising a compound of the invention and a pharmaceutically suitableexcipient.

The compounds of the invention may be used alone or in combination withone or more other biologically active ingredients.

In one aspect the invention provides a combination product comprising apesticidally effective amount of a component A and a pesticidallyeffective amount of component B wherein component A is a compound of theinvention and component B is a compound as described below.

The compounds of the invention may be used in combination withanthelmintic agents. Such anthelmintic agents include, compoundsselected from the macrocyclic lactone class of compounds such asivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin,selamectin, moxidectin, nemadectin and milbemycin derivatives asdescribed in EP-357460, EP-444964 and EP-594291. Additional anthelminticagents include semisynthetic and biosynthetic avermectin/milbemycinderivatives such as those described in U.S. Pat. No. 5,015,630,WO-9415944 and WO-9522552. Additional anthelmintic agents include thebenzimidazoles such as albendazole, cambendazole, fenbendazole,flubendazole, mebendazole, oxfendazole, oxibendazole, parbendazole, andother members of the class. Additional anthelmintic agents includeimidazothiazoles and tetrahydropyrimidines such as tetramisole,levamisole, pyrantel pamoate, oxantel or morantel. Additionalanthelmintic agents include flukicides, such as triclabendazole andclorsulon and the cestocides, such as praziquantel and epsiprantel.

The compounds of the invention may be used in combination withderivatives and analogues of the paraherquamide/marcfortine class ofanthelmintic agents, as well as the antiparasitic oxazolines such asthose disclosed in U.S. Pat. No. 5,478,855, U.S. Pat. No. 4,639,771 andDE-19520936.

The compounds of the invention may be used in combination withderivatives and analogues of the general class of dioxomorpholineantiparasitic agents as described in WO-9615121 and also withanthelmintic active cyclic depsipeptides such as those described inWO-9611945, WO-9319053, WO-9325543, EP-626375, EP-382173, WO-9419334,EP-382173, and EP-503538.

The compounds of the invention may be used in combination with otherectoparasiticides; for example, fipronil; pyrethroids; organophosphates;insect growth regulators such as lufenuron; ecdysone agonists such astebufenozide and the like; neonicotinoids such as imidacloprid and thelike.

The compounds of the invention may be used in combination with terpenealkaloids, for example those described in International PatentApplication Publication Numbers WO95/19363 or WO04/72086, particularlythe compounds disclosed therein.

Other examples of such biologically active compounds that the compoundsof the invention may be used in combination with include but are notrestricted to the following: Organophosphates: acephate, azamethiphos,azinphos-ethyl, azinphos-methyl, bromophos, bromophos-ethyl, cadusafos,chlorethoxyphos, chlorpyrifos, chlorfenvinphos, chlormephos, demeton,demeton-S-methyl, demeton-S-methyl sulphone, dialifos, diazinon,dichlorvos, dicrotophos, dimethoate, disulfoton, ethion, ethoprophos,etrimfos, famphur, fenamiphos, fenitrothion, fensulfothion, fenthion,flupyrazofos, fonofos, formothion, fosthiazate, heptenophos, isazophos,isothioate, isoxathion, malathion, methacriphos, methamidophos,methidathion, methyl-parathion, mevinphos, monocrotophos, naled,omethoate, oxydemeton-methyl, paraoxon, parathion, parathion-methyl,phenthoate, phosalone, phosfolan, phosphocarb, phosmet, phosphamidon,phorate, phoxim, pirimiphos, pirimiphos-methyl, profenofos, propaphos,proetamphos, prothiofos, pyraclofos, pyridapenthion, quinalphos,sulprophos, temephos, terbufos, tebupirimfos, tetrachlorvinphos,thimeton, triazophos, trichlorfon, vamidothion.

Carbamates: alanycarb, aldicarb, 2-sec-butylphenyl methylcarbamate,benfuracarb, carbaryl, carbofuran, carbosulfan, cloethocarb,ethiofencarb, fenoxycarb, fenthiocarb, furathiocarb, HCN-801,isoprocarb, indoxacarb, methiocarb, methomyl,5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl, pirimicarb,propoxur, thiodicarb, thiofanox, triazamate, UC-51717.

Pyrethroids: acrinathin, allethrin, alphametrin, 5-benzyl-3-furylmethyl(E)-(1R)-cis-2,2-dimethyl-3-(2-oxothiolan-3-ylidenemethyl)cyclopropanecarboxylate,bifenthrin, beta-cyfluthrin, cyfluthrin, a-cypermethrin,beta-cypermethrin, bioallethrin, bioallethrin((S)-cyclopentylisomer),bioresmethrin, bifenthrin, NCI-85193, cycloprothrin, cyhalothrin,cythithrin, cyphenothrin, deltamethrin, empenthrin, esfenvalerate,ethofenprox, fenfluthrin, fenpropathrin, fenvalerate, flucythrinate,flumethrin, fluvalinate (D isomer), imiprothrin, cyhalothrin,lambda-cyhalothrin, permethrin, phenothrin, prallethrin, pyrethrins(natural products), resmethrin, tetramethrin, transfluthrin,theta-cypermethrin, silafluofen, t-fluvalinate, tefluthrin,tralomethrin, Zeta-cypermethrin.

Arthropod growth regulators: a) chitin synthesis inhibitors:benzoylureas: chlorfluazuron, diflubenzuron, fluazuron, flucycloxuron,flufenoxuron, hexaflumuron, lufenuron, novaluron, teflubenzuron,triflumuron, buprofezin, diofenolan, hexythiazox, etoxazole,chlorfentazine; b) ecdysone antagonists: halofenozide, methoxyfenozide,tebufenozide; c) juvenoids: pyriproxyfen, methoprene (includingS-methoprene), fenoxycarb; d) lipid biosynthesis inhibitors:spirodiclofen.

Other antiparasitics: acequinocyl, amitraz, AKD-1022, ANS-118,azadirachtin, Bacillus thuringiensis, bensultap, bifenazate, binapacryl,bromopropylate, BTG-504, BTG-505, camphechlor, cartap, chlorobenzilate,chlordimeform, chlorfenapyr, chromafenozide, clothianidine, cyromazine,diacloden, diafenthiuron, DBI-3204, dinactin,dihydroxymethyldihydroxypyrrolidine, dinobuton, dinocap, endosulfan,ethiprole, ethofenprox, fenazaquin, flumite, MTI-800, fenpyroximate,fluacrypyrim, flubenzimine, flubrocythrinate, flufenzine, flufenprox,fluproxyfen, halofenprox, hydramethylnon, IKI-220, kanemite, NC-196,neem guard, nidinorterfuran, nitenpyram, SD-35651, WL-108477, pirydaryl,propargite, protrifenbute, pymethrozine, pyridaben, pyrimidifen,NC-1111, R-195, RH-0345, RH-2485, RYI-210, S-1283, S-1833, SI-8601,silafluofen, silomadine, spinosad, tebufenpyrad, tetradifon,tetranactin, thiacloprid, thiocyclam, thiamethoxam, tolfenpyrad,triazamate, triethoxyspinosyn, trinactin, verbutin, vertalec, YI-5301.

Fungicides: acibenzolar, aldimorph, ampropylfos, andoprim, azaconazole,azoxystrobin, benalaxyl, benomyl, bialaphos, blasticidin-S, Bordeauxmixture, bromuconazole, bupirimate, carpropamid, captafol, captan,carbendazim, chlorfenazole, chloroneb, chloropicrin, chlorothalonil,chlozolinate, copper oxychloride, copper salts, cyflufenamid, cymoxanil,cyproconazole, cyprodinil, cyprofuram, RH-7281, diclocymet,diclobutrazole, diclomezine, dicloran, difenoconazole, RP-407213,dimethomorph, domoxystrobin, diniconazole, diniconazole-M, dodine,edifenphos, epoxiconazole, famoxadone, fenamidone, fenarimol,fenbuconazole, fencaramid, fenpiclonil, fenpropidin, fenpropimorph,fentin acetate, fluazinam, fludioxonil, flumetover, flumorf/flumorlin,fentin hydroxide, fluoxastrobin, fluquinconazole, flusilazole,flutolanil, flutriafol, folpet, fosetyl-aluminium, furalaxyl,furametapyr, hexaconazole, ipconazole, iprobenfos, iprodione,isoprothiolane, kasugamycin, krsoxim-methyl, mancozeb, maneb, mefenoxam,mepronil, metalaxyl, metconazole, metominostrobin/fenominostrobin,metrafenone, myclobutanil, neoasozin, nicobifen, orysastrobin, oxadixyl,penconazole, pencycuron, probenazole, prochloraz, propamocarb,propioconazole, proquinazid, prothioconazole, pyrifenox, pyraclostrobin,pyrimethanil, pyroquilon, quinoxyfen, spiroxamine, sulfur, tebuconazole,tetrconazole, thiabendazole, thifluzamide, thiophanate-methyl, thiram,tiadinil, triadimefon, triadimenol, tricyclazole, trifloxystrobin,triticonazole, validamycin, vinclozin.

Biological agents: Bacillus thuringiensis ssp aizawai, kurstaki,Bacillus thuringiensis delta endotoxin, baculovirus, entomopathogenicbacteria, virus and fungi.

Bactericides: chlortetracycline, oxytetracycline, streptomycin.

Other biological agents: enrofloxacin, febantel, penethamate, moloxicam,cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin,benazepril, pyriprole, cefquinome, florfenicol, buserelin, cefovecin,tulathromycin, ceftiour, carprofen, metaflumizone, praziquarantel,triclabendazole.

When used in combination with other active ingredients, the compounds ofthe invention are preferably used in combination with imidacloprid,enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate,moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, fipronil,ivermectin, omeprazole, tiamulin, benazepril, milbemycin, cyromazine,thiamethoxam, pyriprole, deltamethrin, cefquinome, florfenicol,buserelin, cefovecin, tulathromycin, ceftiour, selamectin, carprofen,metaflumizone, moxidectin, methoprene (including S-methoprene),clorsulon, pyrantel, amitraz, triclabendazole, avermectin, abamectin,emamectin, eprinomectin, doramectin, selamectin, nemadectin,albendazole, cambendazole, fenbendazole, flubendazole, mebendazole,oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole,pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel,fipronil, lufenuron, ecdysone or tebufenozide; more preferably,enrofloxacin, praziquantel, pyrantel embonate, febantel, penethamate,moloxicam, cefalexin, kanamycin, pimobendan, clenbuterol, omeprazole,tiamulin, benazepril, pyriprole, cefquinome, florfenicol, buserelin,cefovecin, tulathromycin, ceftiour, selamectin, carprofen, moxidectin,clorsulon, pyrantel, eprinomectin, doramectin, selamectin, nemadectin,albendazole, cambendazole, fenbendazole, flubendazole, mebendazole,oxfendazole, oxibendazole, parbendazole, tetramisole, levamisole,pyrantel pamoate, oxantel, morantel, triclabendazole, epsiprantel,lufenuron or ecdysone; even more preferably, enrofloxacin, praziquantel,pyrantel embonate, febantel, penethamate, moloxicam, cefalexin,kanamycin, pimobendan, clenbuterol, omeprazole, tiamulin, benazepril,pyriprole, cefquinome, florfenicol, buserelin, cefovecin, tulathromycin,ceftiour, selamectin, carprofen, moxidectin, clorsulon or pyrantel.

Of particular note is a combination where the additional activeingredient has a different site of action from the compound of formulaI. In certain instances, a combination with at least one other parasiticinvertebrate pest control active ingredient having a similar spectrum ofcontrol but a different site of action will be particularly advantageousfor resistance management. Thus, a combination product of the inventionmay comprise a pesticidally effective amount of a compound of formula Iand pesticidally effective amount of at least one additional parasiticinvertebrate pest control active ingredient having a similar spectrum ofcontrol but a different site of action.

One skilled in the art recognizes that because in the environment andunder physiological conditions salts of chemical compounds are inequilibrium with their corresponding non salt forms, salts share thebiological utility of the non salt forms. Thus a wide variety of saltsof compounds of the invention (and active ingredients used incombination with the active ingredients of the invention) may be usefulfor control of invertebrate pests and animal parasites. Salts includeacid-addition salts with inorganic or organic acids such as hydrobromic,hydrochloric, nitric, phosphoric, sulfuric, acetic, butyric, fumaric,lactic, maleic, malonic, oxalic, propionic, salicylic, tartaric,4-toluenesulfonic or valeric acids. The compounds of the invention alsoinclude N-oxides. Accordingly, the invention comprises combinations ofcompounds of the invention including N-oxides and salts thereof and anadditional active ingredient including N-oxides and salts thereof.

The compositions for use in animal health may also contain formulationauxiliaries and additives, known to those skilled in the art asformulation aids (some of which may be considered to also function assolid diluents, liquid diluents or surfactants). Such formulationauxiliaries and additives may control: pH (buffers), foaming duringprocessing (antifoams such polyorganosiloxanes), sedimentation of activeingredients (suspending agents), viscosity (thixotropic thickeners),in-container microbial growth (antimicrobials), product freezing(antifreezes), color (dyes/pigment dispersions), wash-off (film formersor stickers), evaporation (evaporation retardants), and otherformulation attributes. Film formers include, for example, polyvinylacetates, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohols, polyvinyl alcohol copolymers andwaxes. Examples of formulation auxiliaries and additives include thoselisted in McCutcheon's Volume 2: Functional Materials, annualInternational and North American editions published by McCutcheon'sDivision, The Manufacturing Confectioner Publishing Co.; and PCTPublication WO 03/024222.

The compounds of the invention can be applied without other adjuvants,but most often application will be of a formulation comprising one ormore active ingredients with suitable carriers, diluents, andsurfactants and possibly in combination with a food depending on thecontemplated end use. One method of application involves spraying awater dispersion or refined oil solution of the combination products.Compositions with spray oils, spray oil concentrations, spreaderstickers, adjuvants, other solvents, and synergists such as piperonylbutoxide often enhance compound efficacy. Such sprays can be appliedfrom spray containers such as a can, a bottle or other container, eitherby means of a pump or by releasing it from a pressurized container,e.g., a pressurized aerosol spray can. Such spray compositions can takevarious forms, for example, sprays, mists, foams, fumes or fog. Suchspray compositions thus can further comprise propellants, foamingagents, etc. as the case may be. Of note is a spray compositioncomprising a pesticidally effective amount of a compound of theinvention and a carrier. One embodiment of such a spray compositioncomprises a pesticidally effective amount of a compound of the inventionand a propellant. Representative propellants include, but are notlimited to, methane, ethane, propane, butane, isobutane, butene,pentane, isopentane, neopentane, pentene, hydrofluorocarbons,chlorofluorocarbons, dimethyl ether, and mixtures of the foregoing. Ofnote is a spray composition (and a method utilizing such a spraycomposition dispensed from a spray container) used to control at leastone parasitic invertebrate pest selected from the group consisting ofmosquitoes, black flies, stable flies, deer flies, horse flies, wasps,yellow jackets, hornets, ticks, spiders, ants, gnats, and the like,including individually or in combinations.

The controlling of animal parasites includes controlling externalparasites that are parasitic to the surface of the body of the hostanimal (e.g., shoulders, armpits, abdomen, inner part of the thighs) andinternal parasites that are parasitic to the inside of the body of thehost animal (e.g., stomach, intestine, lung, veins, under the skin,lymphatic tissue). External parasitic or disease transmitting pestsinclude, for example, chiggers, ticks, lice, mosquitoes, flies, mitesand fleas. Internal parasites include heartworms, hookworms andhelminths. The compounds of the invention may be particularly suitablefor combating external parasitic pests. The compounds of the inventionmay be suitable for systemic and/or non-systemic control of infestationor infection by parasites on animals.

The compounds of the invention may be suitable for combating parasiticinvertebrate pests that infest animal subjects including those in thewild, livestock and agricultural working animals. Livestock is the termused to refer (singularly or plurally) to a domesticated animalintentionally reared in an agricultural setting to make produce such asfood or fiber, or for its labor; examples of livestock include cattle,sheep, goats, horses, pigs, donkeys, camels, buffalo, rabbits, hens,turkeys, ducks and geese (e.g., raised for meat, milk, butter, eggs,fur, leather, feathers and/or wool). By combating parasites, fatalitiesand performance reduction (in terms of meat, milk, wool, skins, eggs,etc.) are reduced, so that applying the compounds of the inventionallows more economic and simple husbandry of animals.

The compounds of the invention may be suitable for combating parasiticinvertebrate pests that infest companion animals and pets (e.g., dogs,cats, pet birds and aquarium fish), research and experimental animals(e.g., hamsters, guinea pigs, rats and mice), as well as animals raisedfor/in zoos, wild habitats and/or circuses.

In an embodiment of this invention, the animal is preferably avertebrate, and more preferably a mammal, avian or fish. In a particularembodiment, the animal subject is a mammal (including great apes, suchas humans). Other mammalian subjects include primates (e.g., monkeys),bovine (e.g., cattle or dairy cows), porcine (e.g., hogs or pigs), ovine(e.g., goats or sheep), equine (e.g., horses), canine (e.g., dogs),feline (e.g., house cats), camels, deer, donkeys, buffalos, antelopes,rabbits, and rodents (e.g., guinea pigs, squirrels, rats, mice, gerbils,and hamsters). Avians include Anatidae (swans, ducks and geese),Columbidae (e.g., doves and pigeons), Phasianidae (e.g., partridges,grouse and turkeys), Thesienidae (e.g., domestic chickens), Psittacines(e.g., parakeets, macaws, and parrots), game birds, and ratites (e.g.,ostriches).

Birds treated or protected by the compounds of the invention can beassociated with either commercial or noncommercial aviculture. Theseinclude Anatidae, such as swans, geese, and ducks, Columbidae, such asdoves and domestic pigeons, Phasianidae, such as partridge, grouse andturkeys, Thesienidae, such as domestic chickens, and Psittacines, suchas parakeets, macaws and parrots raised for the pet or collector market,among others.

For purposes of the present invention, the term “fish” is understood toinclude without limitation, the Teleosti grouping of fish, i.e.,teleosts. Both the Salmoniformes order (which includes the Salmonidaefamily) and the Perciformes order (which includes the Centrarchidaefamily) are contained within the Teleosti grouping. Examples ofpotential fish recipients include the Salmonidae, Serranidae, Sparidae,Cichlidae, and Centrarchidae, among others.

Other animals are also contemplated to benefit from the inventivemethods, including marsupials (such as kangaroos), reptiles (such asfarmed turtles), and other economically important domestic animals forwhich the inventive methods are safe and effective in treating orpreventing parasite infection or infestation.

Examples of parasitic invertebrate pests controlled by administering apesticidally effective amount of the compounds of the invention to ananimal to be protected include ectoparasites (arthropods, acarines,etc.) and endoparasites (helminths, e.g., nematodes, trematodes,cestodes, acanthocephalans, etc.).

The disease or group of diseases described generally as helminthiasis isdue to infection of an animal host with parasitic worms known ashelminths. The term ‘helminths’ is meant to include nematodes,trematodes, cestodes and acanthocephalans. Helminthiasis is a prevalentand serious economic problem with domesticated animals such as swine,sheep, horses, cattle, goats, dogs, cats and poultry.

Among the helminths, the group of worms described as nematodes causeswidespread and at times serious infection in various species of animals.Nematodes that are contemplated to be treated by the compounds of theinvention include, without limitation, the following genera:Acanthocheilonema, Aelurostrongylus, Ancylostoma, Angiostrongylus,Ascaridia, Ascaris, Brugia, Bunostomum, Capillaria, Chabertia, Cooperia,Crenosoma, Dictyocaulus, Dioctophyme, Dipetalonema, Diphyllobothrium,Dirofilaria, Dracunculus, Enterobius, Filaroides, Haemonchus, Heterakis,Lagochilascaris, Loa, Mansonella, Muellerius, Necator, Nematodirus,Oesophagostomum, Ostertagia, Oxyuris, Parafilaria, Parascaris,Physaloptera, Protostrongylus, Setaria, Spirocerca, Stephanofilaria,Strongyloides, Strongylus, Thelazia, Toxascaris, Toxocara, Trichinella,Trichonema, Trichostrongylus, Trichuris, Uncinaria and Wuchereria.

Of the above, the most common genera of nematodes infecting the animalsreferred to above are Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris andParascaris. Certain of these, such as Nematodirus, Cooperia andOesophagostomum attack primarily the intestinal tract while others, suchas Haemonchus and Ostertagia, are more prevalent in the stomach whileothers such as Dictyocaulus are found in the lungs. Still otherparasites may be located in other tissues such as the heart and bloodvessels, subcutaneous and lymphatic tissue and the like.

Trematodes that are contemplated to be treated by the invention and bythe inventive methods include, without limitation, the following genera:Alaria, Fasciola, Nanophyetus, Opisthorchis, Paragonimus andSchistosoma.

Cestodes that are contemplated to be treated by the invention and by theinventive methods include, without limitation, the following genera:Diphyllobothrium, Diplydium, Spirometra and Taenia.

The most common genera of parasites of the gastrointestinal tract ofhumans are Ancylostoma, Necator, Ascaris, Strongy hides, Trichinella,Capillaria, Trichuris and Enterobius. Other medically important generaof parasites which are found in the blood or other tissues and organsoutside the gastrointestinal tract are the filarial worms such asWuchereria, Brugia, Onchocerca and Loa, as well as Dracunculus and extraintestinal stages of the intestinal worms Strongyloides and Trichinella.

Numerous other helminth genera and species are known to the art, and arealso contemplated to be treated by the compounds of the invention. Theseare enumerated in great detail in Textbook of Veterinary ClinicalParasitology, Volume 1, Helminths, E. J. L. Soulsby, F. A. Davis Co.,Philadelphia, Pa.; Helminths, Arthropods and Protozoa, (6^(th)Edition ofMonnig's Veterinary Helminthology and Entomology), E. J. L. Soulsby,Williams and Wilkins Co., Baltimore, Md.

The compounds of the invention may be effective against a number ofanimal ectoparasites (e.g., arthropod ectoparasites of mammals andbirds).

Insect and acarine pests include, e.g., biting insects such as flies andmosquitoes, mites, ticks, lice, fleas, true bugs, parasitic maggots, andthe like.

Adult flies include, e.g., the horn fly or Haematobia irritans, thehorse fly or Tabanus spp., the stable fly or Stomoxys calcitrans, theblack fly or Simulium spp., the deer fly or Chrysops spp., the louse flyor Melophagus ovinus, and the tsetse fly or Glossina spp. Parasitic flymaggots include, e.g., the bot fly (Oestrus ovis and Cuterebra spp.),the blow fly or Phaenicia spp., the screwworm or Cochliomyiahominivorax, the cattle grub or Hypoderma spp., the fleeceworm and theGastrophilus of horses. Mosquitoes include, for example, Culex spp.,Anopheles spp. and Aedes spp.

Mites include Mesostigmalphatalpha spp. e.g., mesostigmatids such as thechicken mite, Dermalphanyssus galphallinalphae; itch or scab mites suchas Sarcoptidae spp. for example, Salpharcoptes scalphabiei; mange mitessuch as Psoroptidae spp. including Chorioptes bovis and Psoroptes ovis;chiggers e.g., Trombiculidae spp. for example the North Americanchigger, Trombiculalpha alphalfreddugesi.

Ticks include, e.g., soft-bodied ticks including Argasidae spp. forexample Argalphas spp. and Ornithodoros spp.; hard-bodied ticksincluding Ixodidae spp., for example Rhipicephalphalus sanguineus,Dermacentor variabilis, Dermacentor andersoni, Amblyomma americanum,Ixodes scapularis and other Rhipicephalus spp. (including the formerBoophilus genera).

Lice include, e.g., sucking lice, e.g., Menopon spp. and Bovicola spp.;biting lice, e.g., Haematopinus spp., Linognathus spp. and Solenopotesspp.

Fleas include, e.g., Ctenocephalides spp., such as dog flea(Ctenocephalides canis) and cat flea (Ctenocephalidesfelis); Xenopsyllaspp. such as oriental rat flea (Xenopsylla cheopis); and Pulex spp. suchas human flea (Pulex irritans).

True bugs include, e.g., Cimicidae or e.g., the common bed bug (Cimexlectularius); Triatominae spp. including triatomid bugs also known askissing bugs; for example Rhodnius prolixus and Triatoma spp.

Generally, flies, fleas, lice, mosquitoes, gnats, mites, ticks andhelminths cause tremendous losses to the livestock and companion animalsectors. Arthropod parasites also are a nuisance to humans and canvector disease-causing organisms in humans and animals.

Numerous other parasitic invertebrate pests are known to the art, andare also contemplated to be treated by the compounds of the invention.These are enumerated in great detail in Medical and VeterinaryEntomology, D. S. Kettle, John Wiley AND Sons, New York and Toronto;Control of Arthropod Pests of Livestock: A Review of Technology, R. O.Drummand, J. E. George, and S. E. Kunz, CRC Press, Boca Raton, FIa.

The compounds of the invention may also be effective againstectoparasites including: flies such as Haematobia (Lyperosia) irritans(horn fly), Simulium spp. (blackfly), Glossina spp. (tsetse flies),Hydrotaea irritans (head fly), Musca autumnalis (face fly), Muscadomestica (house fly), Morellia simplex (sweat fly), Tabanus spp. (horsefly), Hypoderma bovis, Hypoderma lineatum, Lucilia sericata, Luciliacuprina (green blowfly), Calliphora spp. (blowfly), Protophormia spp.,Oestrus ovis (nasal botfly), Culicoides spp. (midges), Hippoboscaequine, Gastrophilus intestinalis, Gastrophilus haemorrhoidalis andGastrophilus nasalis; lice such as Bovicola (Damalinia) bovis, Bovicolaequi, Haematopinus asini, Felicola subrostratus, Heterodoxus spiniger,Lignonathus setosus and Trichodectes canis; keds such as Melophagusovinus; and mites such as Psoroptes spp., Sarcoptes scabei, Chorioptesbovis, Demodex equi, Cheyletiella spp., Notoedres cati, Trombicula spp.and Otodectes cyanotis (ear mites).

Treatments of the invention are by conventional means such as by enteraladministration in the form of, for example, tablets, capsules, drinks,drenching preparations, granulates, pastes, boli, feed-throughprocedures, or suppositories; or by parenteral administration, such as,for example, by injection (including intramuscular, subcutaneous,intravenous, intraperitoneal) or implants; or by nasal administration.

When compounds of the invention are applied in combination with anadditional biologically active ingredient, they may be administeredseparately e.g. as separate compositions. In this case, the biologicallyactive ingredients may be administered simultaneously or sequentially.Alternatively, the biologically active ingredients may be components ofone composition.

The compounds of the invention may be administered in a controlledrelease form, for example in subcutaneous or orally adminstered slowrelease formulations.

Typically a parasiticidal composition according to the present inventioncomprises a compound of the invention, optionally in combination with anadditional biologically active ingredient, or N-oxides or salts thereof,with one or more pharmaceutically or veterinarily acceptable carrierscomprising excipients and auxiliaries selected with regard to theintended route of administration (e.g., oral or parenteraladministration such as injection) and in accordance with standardpractice. In addition, a suitable carrier is selected on the basis ofcompatibility with the one or more active ingredients in thecomposition, including such considerations as stability relative to pHand moisture content. Therefore of note are compounds of the inventionfor protecting an animal from an invertebrate parasitic pest comprisinga parasitically effective amount of a compound of the invention,optionally in combination with an additional biologically activeingredient and at least one carrier.

For parenteral administration including intravenous, intramuscular andsubcutaneous injection, the compounds of the invention can be formulatedin suspension, solution or emulsion in oily or aqueous vehicles, and maycontain adjuncts such as suspending, stabilizing and/or dispersingagents.

The compounds of the invention may also be formulated for bolusinjection or continuous infusion. Pharmaceutical compositions forinjection include aqueous solutions of water-soluble forms of activeingredients (e.g., a salt of an active compound), preferably inphysiologically compatible buffers containing other excipients orauxiliaries as are known in the art of pharmaceutical formulation.Additionally, suspensions of the active compounds may be prepared in alipophilic vehicle. Suitable lipophilic vehicles include fatty oils suchas sesame oil, synthetic fatty acid esters such as ethyl oleate andtriglycerides, or materials such as liposomes.

Aqueous injection suspensions may contain substances that increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Formulations for injection may be presented inunit dosage form, e.g., in ampoules or in multi-dose containers.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile, pyrogen-free water,before use.

In addition to the formulations described supra, the compounds of theinvention may also be formulated as a depot preparation. Such longacting formulations may be administered by implantation (for example,subcutaneously or intramuscularly) or by intramuscular or subcutaneousinjection.

The compounds of the invention may be formulated for this route ofadministration with suitable polymeric or hydrophobic materials (forinstance, in an emulsion with a pharmacologically acceptable oil), withion exchange resins, or as a sparingly soluble derivative such as,without limitation, a sparingly soluble salt.

For administration by inhalation, the compounds of the invention can bedelivered in the form of an aerosol spray using a pressurized pack or anebulizer and a suitable propellant, e.g., without limitation,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be controlled by providing avalve to deliver a metered amount.

Capsules and cartridges of, for example, gelatin for use in an inhaleror insufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds of the invention may have favourable pharmacokinetic andpharmacodynamic properties providing systemic availability from oraladministration and ingestion. Therefore after ingestion by the animal tobe protected, parasiticidally effective concentrations of a compound ofthe invention in the bloodstream may protect the treated animal fromblood-sucking pests such as fleas, ticks and lice. Therefore of note isa composition for protecting an animal from an invertebrate parasitepest in a form for oral administration (i.e. comprising, in addition toa parasiticidally effective amount of a compound of the invention, oneor more carriers selected from binders and fillers suitable for oraladministration and feed concentrate carriers).

For oral administration in the form of solutions (the most readilyavailable form for absorption), emulsions, suspensions, pastes, gels,capsules, tablets, boluses, powders, granules, rumen-retention andfeed/water/lick blocks, the compounds of the invention can be formulatedwith binders/fillers known in the art to be suitable for oraladministration compositions, such as sugars and sugar derivatives (e.g.,lactose, sucrose, mannitol, sorbitol), starch (e.g., maize starch, wheatstarch, rice starch, potato starch), cellulose and derivatives (e.g.,methylcellulose, carboxymethylcellulose, ethylhydroxycellulose), proteinderivatives (e.g., zein, gelatin), and synthetic polymers (e.g.,polyvinyl alcohol, polyvinylpyrrolidone). If desired, lubricants (e.g.,magnesium stearate), disintegrating agents (e.g., cross-linkedpolyvinylpyrrolidinone, agar, alginic acid) and dyes or pigments can beadded. Pastes and gels often also contain adhesives (e.g., acacia,alginic acid, bentonite, cellulose, xanthan gum, colloidal magnesiumaluminum silicate) to aid in keeping the composition in contact with theoral cavity and not being easily ejected.

In one embodiment a composition of the present invention is formulatedinto a chewable and/or edible product (e.g., a chewable treat or edibletablet). Such a product would ideally have a taste, texture and/or aromafavored by the animal to be protected so as to facilitate oraladministration of the compounds of the invention.

If the parasiticidal compositions are in the form of feed concentrates,the carrier is typically selected from high-performance feed, feedcereals or protein concentrates. Such feed concentrate-containingcompositions can, in addition to the parasiticidal active ingredients,comprise additives promoting animal health or growth, improving qualityof meat from animals for slaughter or otherwise useful to animalhusbandry.

These additives can include, for example, vitamins, antibiotics,chemotherapeutics, bacteriostats, fungistats, coccidiostats andhormones.

The compound of the invention may also be formulated in rectalcompositions such as suppositories or retention enemas, using, e.g.,conventional suppository bases such as cocoa butter or other glycerides.

The formulations for the method of this invention may include anantioxidant, such asBHT (butylated hydroxytoluene). The antioxidant isgenerally present in amounts of at 0.1-5 percent (wt/vol). Some of theformulations require a solubilizer, such as oleic acid, to dissolve theactive agent, particularly if spinosad is included. Common spreadingagents used in these pour-on formulations include isopropyl myristate,isopropyl palmitate, caprylic/capric acid esters of saturated C₁₂-C₁₈fatty alcohols, oleic acid, oleyl ester, ethyl oleate, triglycerides,silicone oils and dipropylene glycol methyl ether. The pour-onformulations for the method of this invention are prepared according toknown techniques.

Where the pour-on is a solution, the parasiticide/insecticide is mixedwith the carrier or vehicle, using heat and stirring if required.Auxiliary or additional ingredients can be added to the mixture ofactive agent and carrier, or they can be mixed with the active agentprior to the addition of the carrier. Pour-on formulations in the formof emulsions or suspensions are similarly prepared using knowntechniques.

Other delivery systems for relatively hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well-knownexamples of delivery vehicles or carriers for hydrophobic drugs. Inaddition, organic solvents such as dimethylsulfoxide may be used, ifneeded.

The rate of application required for effective parasitic invertebratepest control (e.g. “pesticidally effective amount”) will depend on suchfactors as the species of parasitic invertebrate pest to be controlled,the pest's life cycle, life stage, its size, location, time of year,host crop or animal, feeding behavior, mating behavior, ambientmoisture, temperature, and the like. One skilled in the art can easilydetermine the pesticidally effective amount necessary for the desiredlevel of parasitic invertebrate pest control.

In general for veterinary use, the compounds of the invention areadministered in a pesticidally effective amount to an animal,particularly a homeothermic animal, to be protected from parasiticinvertebrate pests.

A pesticidally effective amount is the amount of active ingredientneeded to achieve an observable effect diminishing the occurrence oractivity of the target parasitic invertebrate pest. One skilled in theart will appreciate that the pesticidally effective dose can vary forthe various compounds and compositions useful for the method of thepresent invention, the desired pesticidal effect and duration, thetarget parasitic invertebrate pest species, the animal to be protected,the mode of application and the like, and the amount needed to achieve aparticular result can be determined through simple experimentation.

For oral or parenteral administration to animals, a dose of thecompositions of the present invention administered at suitable intervalstypically ranges from about 0.01 mg/kg to about 100 mg/kg, andpreferably from about 0.01 mg/kg to about 30 mg/kg of animal bodyweight.

Suitable intervals for the administration of the compositions of thepresent invention to animals range from about daily to about yearly. Ofnote are administration intervals ranging from about weekly to aboutonce every 6 months. Of particular note are monthly administrationintervals (i.e. administering the compounds to the animal once everymonth).

The following Examples illustrate, but do not limit, the invention.

The following abbreviations were used in this section: s=singlet;bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet;t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet;Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point;RT=retention time, [M+H]⁺=molecular mass of the molecular cation,[M−H]⁻=molecular mass of the molecular anion.The following LC-MS methods were used to characterize the compounds:

Method A

MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, source temperature (°C.) 100, desolvation temperature (° C.) 250, cone gas flow (L/Hr) 50,desolvation gas flow (L/Hr) 400, mass range: 150 to 1000 Da. LC HP 1100HPLC from Agilent: solvent degasser, quaternary pump, heated columncompartment and diode-array detector. Column: Phenomenex Gemini C18,length (mm) 30, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 60, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.05% v/v formic acid in water and B = 0.04% v/v formicacid in acetonitrile/methanol (4:1). Time (min) A % B % Flow (ml/min)0.0 95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0 100 1.7 2.9 95 5.0 1.7

Method B

MS ZMD Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 150, desolvation temperature (° C.) 320, conegas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to800 Da. LC Alliance 2795 LC HPLC from Waters: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 80 20 1.7 5.0 0.0100 1.7 5.6 0.0 100 1.7 6.0 80 20 1.7

Method C

MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 100, desolvation temperature (° C.) 200, conegas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to800 Da. LC 1100er Series HPLC from Agilent: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 90 10 1.7 5.5 0.0100 1.7 5.8 0.0 100 1.7 5.9 90 10 1.7

Method D

MS ZMD Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 150, desolvation temperature (° C.) 320, conegas flow (L/Hr) 50, desolvation gas flow (L/Hr) 400, mass range: 150 to800 Da. LC Alliance 2795 LC HPLC from Waters: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 80 20 1.7 2.5 0.0100 1.7 2.8 0.0 100 1.7 2.9 80 20 1.7

Method E

MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: positiveionization, capillary (kV) 3.00, cone (V) 30.00, extractor (V) 3.00,source temperature (° C.) 100, desolvation temperature (° C.) 200, conegas flow (L/Hr) 200, desolvation gas flow (L/Hr) 250, mass range: 150 to800 Da. LC 1100er Series HPLC from Agilent: quaternary pump, heatedcolumn compartment and diode-array detector. Column: Waters Atlantisdc18, length (mm) 20, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 40, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.1% v/v formic acid in water and B = 0.1% v/v formic acidin acetonitrile. Time (min) A % B % Flow (ml/min) 0.0 80 20 1.7 2.5 0.0100 1.7 2.8 0.0 100 1.7 2.9 80 20 1.7

Method F

MS ZQ Mass Spectrometer from Waters (single quadrupole massspectrometer), ionization method: electrospray, polarity: negativeionization, capillary (kV) 3.00, cone (V) 45.00, source temperature (°C.) 100, desolvation temperature (° C.) 250, cone gas flow (L/Hr) 50,desolvation gas flow (L/Hr) 400, mass range: 150 to 1000 Da. LC HP 1100HPLC from Agilent: solvent degasser, binary pump, heated columncompartment and diode-array detector. Column: Phenomenex Gemini C18,length (mm) 30, internal diameter (mm) 3, particle size (μm) 3,temperature (° C.) 60, DAD wavelength range (nm): 200 to 500, solventgradient: A = 0.05% v/v formic acid in water and B = 0.04% v/v formicacid in acetonitrile/methanol (4:1). Time (min) A % B % Flow (ml/min)0.0 95 5.0 1.7 2.0 0.0 100 1.7 2.8 0.0 100 1.7 2.9 95 5.0 1.7 3.1 95 51.7

Method G

MS Thermo Finnigan Surveyor MSQ PLUS (single quadrupole massspectrometer), ionization method: Chemical Ionization, polarity:positive and negative simultaneous ionization, capillary (kV) 4.00, cone(V) 50.00, source temperature (° C.) 350, mass range: 110 to 800 Da. LCThermo Finnigan Surveyor LC: solvent degasser, quaternary pump, heatedcolumn compartment and diode-array detector. Column: XTerra RP18, length(mm) 50, internal diameter (mm) 4.6, particle size (μm) 3.5, temperature(° C.) 30, DAD wavelength range (nm): 200 to 400, solvent gradient: A =0.05% v/v formic acid in water and B = 0.05% v/v formic acid inacetonitrile Time (min) A % B % Flow (ml/min) 0.0 90.0 10.0 1.7 3.2 10.090.0 1.7 5.0 10.0 90.0 1.7 5.2 90.0 10.0 1.7 6.0 90.0 10.0 1.7

Method H

CHIRAL Alliance 2695 HPLC from Waters: solvent degasser, binary HPLCpump, heated column compartment and diode-array detector Column:Chiralpak IC, length (mm) 250, internal diameter (mm) 4.6, particle size(μ) 5, wavelength (nm): 220 nm, temperature (° C.) 30, solvent:Isocratic isopropyl alcohol: heptane 20:80, injection volume 50 uL, flow(ml/min) 1.

Method J

MS Waters ACQUITY SQD Mass Spectrometer from Waters (Single quadrupolemass spectrometer) Ionisation method: Electrospray Polarity: positiveions Capillary (kV) 3.00, Cone (V) 20.00, Extractor (V) 3.00, SourceTemperature (° C.) 150, Desolvation Temperature (° C.) 400, Cone GasFlow (L/Hr) 60, Desolvation Gas Flow (L/Hr) 700 Mass range: 100 to 800Da DAD Wavelength range (nm): 210 to 400 LC Waters ACQUITY UPLC with thefollowing HPLC gradient conditions (Solvent A: Water/Methanol 9:1, 0.1%formic acid and Solvent B: Acetonitrile, 0.1% formic acid) Time(minutes) A (%) B (%) Flow rate (ml/min) 0 100 0 0.75 2.5 0 100 0.75 2.80 100 0.75 3.0 100 0 0.75 Type of column: Waters ACQUITY UPLC HSS T3;Column length: 30 mm; Internal diameter of column: 2.1 mm; ParticleSize: 1.8 micron; Temperature: 60° C.

Method K

CHIRAL Alliance 2695 HPLC from Waters: solvent degasser, binary HPLCpump, heated column compartment and diode-array detector Column:Chiralpak IB, length (mm) 250, internal diameter (mm) 4.6, particle size(μ) 5, wavelength (nm): 270 nm, temperature (° C.) 30, solvent:Isocratic isopropyl alcohol:heptanes:diethylamine 30:70:0.1, injectionvolume 50 uL, flow (ml/min) 1.

EXAMPLE 14-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[1,2]dithiolan-4-yl-2-methyl-benzamide(compound A1)

Step A: Thioacetic acidS-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester

Methanesulfonic acid2-tert-butoxycarbonylamino-3-methanesulfonyloxy-propyl ester (Synthesis(1998), (8), 1113-1118) in dimethylformamide (5 ml) and potassiumthioacetate (685 mg) in dimethylformamide (5 ml) were added dropwise.The reaction was stirred overnight at room temperature then poured intowater. A yellow-brown solid precipitated which was filtered and washedwith water to give 220 mg of the title product. The aqueous phase wasextracted with diethyl ether, the organic phase was dried over sodiumsulfate, filtered and evaporated in vacuo to give another 110 mg of thetitle product. ¹H-NMR (CDCl₃, 400 MHz): 4.80 (m, 1H), 3.90 (m, 1H), 3.10(m, 4H), 2.40 (s, 6H), 1.40 (s, 9H).

Step B: [1,2]Dithiolan-4-yl-carbamic acid tert-butyl ester

A solution of thioacetic acidS-(3-acetylsulfanyl-2-tert-butoxycarbonylamino-propyl) ester (330 mg) inethanol (5 ml) was treated with 2.5 ml of 1N sodium hydroxide for 1 hourat room temperature. The yellow solid turned green-brown. The reactionmixture was diluted with dichloromethane (25 ml) and then an aqueoussolution of 0.1M iodine (10 ml) was added dropwise. The reaction mixturewas stirred at room temperature for 1 hour and quenched by addition of1M sodium bisulfite solution. The organic layer was separated, washedwith water, dried over sodium sulfate and the solvent evaporated invacuo to afford the title product (170 mg). ¹H-NMR (CDCl₃, 400 MHz):5.00 (br s, 1H), 4.90 (m, 1H), 3.15 (d, 2H), 3.05 (d, 2H), 1.40 (s, 9H).

Step C: [1,2]Dithiolan-4-ylamine

The BOC protecting group was removed as described in Example 3, Step Bto afford the title compound (trifluoroacetic acid salt), which was useddirectly in the next step.

Step D:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[1,2]dithiolan-4-yl-2-methyl-benzamide

Amide coupling was performed as described in Example 3, Step C to affordthe title compound as a solid (40 mg). M.p. 73° C.; LCMS (Method F) 2.20min, M−H 519/521. ¹H-NMR (CDCl₃, 400 MHz): 7.50-7.30 (m, 6H), 6.20 (m,1H), 5.35 (m, 1H), 4.00 (d, 1H), 3.60 (d, 1H), 3.30 (m, 2H), 3.20 (m,2H), 2.40 (s, 3H).

EXAMPLE 24-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B1)

Oxalyl chloride (0.122 ml) was added to a solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (0.5 g) (prepared according to WO 2009/080250) in dichloromethane(3 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) thereaction mixture was stirred at ambient temperature for 18 hours. Thereaction mixture was concentrated to give the acid chloride as a yellowsolid, which was used in the next step without further purification.

D-cycloserine (21 mg) was added to a solution of the acid chloride (45mg) and triethylamine (0.1 ml) in toluene (2 ml). The reaction mixturewas stirred at 50° C. for 16 hours. The reaction mixture was dilutedwith water and ethyl acetate and the phases were separated. The organicphase was washed twice with water, dried over sodium sulfate andconcentrated. The residue was purified by chromatography on silica gel(eluent: dichloromethane/methanol 5%) to give the title compound (28 mg)as a colorless solid. ¹H-NMR (CDCl₃, 400 MHz): 8.60 (s, br., 1H),7.60-7.45 (m, 6H), 6.40 (s, 1H), 5.05 (m, 1H), 4.85 (m, 1H), 4.20 (t,1H), 4.05 (d, 1H), 3.70 (d, 1H), 2.50 (s, 3H) ppm.

EXAMPLE 34-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B2) Step A: ((R)-2-Methyl-3-oxo-isoxazolidin-4-yl)-carbamicacid tert-butyl ester

(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (1.01 g,prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002,50(4) 554-557) was dissolved in dimethylformamide (5 ml), the solutionwas cooled to 0° C. and 616 mg of potassium t-butoxide was addedportionwise. The reaction mixture was stirred at 0° C. for 1 hour then710 mg methylene iodide was added and the reaction mixture was stirredfor 3 hours at room temperature. The reaction mixture was poured intowater and extracted with diethyl ether. The organic phase was thenwashed several times with water, dried over sodium sulphate and thesolvent removed in vacuo. Crude((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester(140 mg) was obtained as a white solid. LCMS (method A) 1.11 min,MH⁺217; ¹H-NMR (CDCl₃, 400 MHz): 5.20 (m, 1H), 4.70 (m, 1H), 4.55 (m,1H), 4.00 (dd, 1H), 3.20 (s, 3H), 1.40 (s, 9H).

Step B: (R)-4-Amino-2-methyl-isoxazolidin-3-one

((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester ofStep A (108 mg) was dissolved in dichloromethane (5 ml) and treated withtrifluoroacetic acid (0.2 ml). The reaction mixture was stirred at roomtemperature for 1 hour and the solvent removed in vacuo to afford(R)-4-Amino-2-methyl-isoxazolidin-3-one (trifluoroacetic acid salt),which was used directly in the next step.

Step C:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-methyl-3-oxo-isoxazolidin-4-yl)-benzamide

To a suspension of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid (175 mg, prepared as described in WO2009/080250) in dichloromethane(5 ml) was added oxalyl chloride (0.05 ml) and then one drop ofdimethylformamide. The reaction mixture stirred at room temperature for2 hours 30 minutes, and the solvent was evaporated in vacuo to give apink solid (acid chloride, 170 mg). The acid chloride thus obtained wasdissolved in dichloromethane (2 ml) and the resulting solution was addeddropwise to a solution of triethylamine (0.35 ml) and(R)-4-Amino-2-methyl-isoxazolidin-3-one (obtained in Step B) indichloromethane (3 ml) at room temperature, under argon. The reactionwas stirred overnight at room temperature, diluted with water, andextracted with ethyl acetate. The organic phase was washed two timeswith water, dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. Purification by column chromatography (eluentcyclohexane/ethyl acetate) afforded the title compound as a solid (70mg). M.p. 87° C.; LCMS (Method A) 1.99 min, MH⁺516/518. ¹H-NMR (CDCl₃,400 MHz): 7.60-7.40 (m, 6H), 6.45 (m, 1H), 5.00 (t, 1H), 4.87 (m, 1H),4.10 (m, 2H), 3.70 (d, 1H), 3.25 (s, 3H), 2.50 (s, 3H).

The following compounds were prepared following a similar method to thatdescribed in Example 3:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-propargyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B3) (using propargyl bromide as an alkylating agent in StepA);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-benzyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B4) (using benzyl bromide as an alkylating agent in Step A);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2,2,2-trifluoroethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B5) (using 2,2,2-trifluoroethyl trifluoromethanesulfonate asalkylating agent in Step A);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-methyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound E1) (starting from (S)-cycloserine)

EXAMPLE 44-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B6) Step A: ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamicacid tert-butyl ester

(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g,prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002,50(4) 554-557) was dissolved in acetonitrile (20 ml) then potassiumcarbonate (0.69 g), potassium iodide (0.175 g) and bromoethane (0.13 g)were added. The reaction was heated under microwave irradiation for 1hour at 140° C. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with water, brine andthen dried over sodium sulphate. The solvent was removed in vacuo andthe crude product was purified by column chromatography (eluentcyclohexane/ethyl acetate) to afford((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester asa yellow solid. LCMS (method A) 1.29 min, MH⁺ (−BOC) 131; ¹H-NMR (CDCl₃,400 MHz): 5.10 (m, 1H), 4.75 (m, 1H), 4.55 (m, 1H), 3.95 (m, 1H), 3.60(m, 2H), 1.50 (s, 9H), 1.20 (m, 3H).

Step B: (R)-4-Amino-2-ethyl-isoxazolidin-3-one

The BOC protecting group was removed as described in Example 3, Step Bto afford (R)-4-amino-2-ethyl-isoxazolidin-3-one (trifluoroacetic acidsalt), which was used directly in the next step.

Step C:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide

Amide coupling was performed as described in Example 3, Step C to affordthe title compound as a solid (160 mg). M.p. 140° C.; LCMS (Method A)2.05 min, M−H 528/530. ¹H-NMR (CDCl₃, 400 MHz): 7.60-7.40 (m, 6H), 6.45(br s, 1H), 5.00 (t, 1H), 4.85 (dt, 1H), 4.10 (d, 1H), 4.00 (dd, 1H),3.70 (d, 1H), 3.60 (m, 2H), 2.50 (s, 3H), 1.25 (m, 3H).

The following compounds were prepared following a similar method to thatdescribed in Example 1:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2-methoxyethyl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B7) (using 2-bromo-1-methoxy-ethane as alkylating agent inStep A);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-butyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound B8) (using butyl bromide as alkylating agent in Step A);4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C1),4-[5-(3,5-Dichloro-4-bromo-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C2);4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C3);4-[5-(3,5-trifluoromethyl-4-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C4);4-[5-(3-chloro-5-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C5);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound E2) (starting from (S)-cycloserine).

When this reaction was carried out to obtain4-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C1), it was possible to separate the two diastereoisomers byprecipitation after the work up. The crude mixture was stirred withdiethyl ether and a solid precipitated out of the solution. The solid(enriched in 1 diastereomer) was analysed by chiral HPLC (method K):9.72 min (93.8%), 16.6 min (06.17%). The filtrate (enriched in the otherdiastereomer) was also analysed by chiral HPLC (method K): 9.99 min(11.53%), 16.6 min (85.16%).

Similarly when this reaction was carried out to obtain4-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(compound C3), it was possible to separate the two diastereoisomers byprecipitation after the work up. The crude mixture was stirred withdiethyl ether and a solid precipitated out of the solution. The solid(enriched in 1 diastereomer) was analysed by chiral HPLC (method K):8.88 min (88.87%), 15.98 min (05.95%). The filtrate (enriched in theother diastereomer) was also analysed by chiral HPLC (method K): 8.61min (24.10%), 12.25 min (74.49%).

EXAMPLE 54-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2-hydroxy-ethyl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B9) Step A:((R)-2-(hydroxy-ethyl)-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butylester

(3-Oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.2 g,prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002,50(4) 554-557) was dissolved in acetonitrile (20 ml), then potassiumcarbonate (0.69 g), potassium iodide (0.175 g) and 2-bromoethanol (0.137g) were added. The reaction was stirred at room temperature for 1 hour.The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed with water, brine and then dried oversodium sulphate. The solvent was removed in vacuo and the crude productwas purified by column chromatography (eluent cyclohexane/ethyl acetate)to afford ((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-carbamic acidtert-butyl ester as a yellow solid. LCMS (method A) 1.05 min, MH⁺259;¹H-NMR (CDCl₃, 400 MHz): 5.55 (br s, 1H), 4.65 (m, 2H), 4.10 (t, 1H),3.80 (m, 1H), 3.20 (br s, 1H), 1.50 (s, 9H), 1.20 (m, 3H).

Step B: (R)-4-Amino-2-(2-hydroxyethyl)-isoxazolidin-3-one

The BOC protecting group was removed as described in Example 3, Step Bto afford (R)-4-amino-2-(2-hydroxyethyl)-isoxazolidin-3-one(trifluoroacetic acid salt), which was used directly in the next step.

Step C:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2-hydroxyethyl)-3-oxo-isoxazolidin-4-yl)-benzamide

Amide coupling was performed as described in Example 3, Step C to affordthe title compound as a solid (24 mg). M.p. 78° C.; LCMS (Method A) 1.94min, M−H 544/550.

EXAMPLE 64-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(thietan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B10) Step A:((R)-2-(thietan-3yl)-3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butylester

A solution of triphenylphosphine (0.79 g) in THF (22 ml) was cooledunder argon to −10° C. Diethylazodicarboxylate (DEAD, 1.57 g) was addeddropwise then thietan-3-ol (0.4 g) and(3-oxo-isoxazolidin-4-yl)-carbamic acid tert-butyl ester (0.27 g,prepared from (D)-cycloserine as described in Chem. Pharm. Bull. 2002,50(4) 554-557). The reaction mixture was stirred at room temperature for24 hours then the solvent was removed in vacuo. The crude product waspurified by column chromatography (eluent cyclohexane/ethyl acetate) toafford the title product as a white solid (51 mg). ¹H-NMR (CDCl₃, 400MHz): 5.45 (q, 1H), 5.05 (m, 1H), 4.90 (m, 1H), 4.50 (t, 1H), 4.10 (dd,1H), 3.55 (m, 2H), 3.40 (m, 2H), 1.50 (s, 9H).

Step B: (R)-4-Amino-2-(thietan-3-yl)-isoxazolidin-3-one

Using the product obtained in Step A (43 mg), the BOC protecting groupwas removed as described in Example 3, Step B to afford the titleproduct, which was used directly in the next step. LCMS (Method A) 0.17min, M−H 175.

Step C:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(thietan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide

Amide coupling was performed as described in Example 3, Step C to affordthe title compound as a yellow resin (10 mg); LCMS (Method A) 2.13 min,M−H 573/574.

The following compounds were prepared following a similar method to thatdescribed in Example 6:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(cyclobutyl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B11);4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(oxetan-3-yl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound B12)

EXAMPLE 7 General Method for Preparing the Compounds of the Invention inParallel

To a solution of4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-3-oxo-isoxazolidin-4-yl)-benzamide(30 μmol) in N,N-dimethylformamide (“DMF”) (0.5 ml) was added a solutionof an alkylhalogenide of formula R—X (32 μmol) in N,N-dimethylformamide(“DMF”) (0.3 ml) followed by addition of potassium carbonate (80 μmol).The reaction mixture was stirred at ambient temperature for 16 hours.Then the reaction mixture was separated by HPLC. This method was used toprepare a number of compounds (Compound Nos. B13 to B29 of Table B) inparallel.

EXAMPLE 84-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-2lambda*4*-[1,2]oxathiolan-4-yl)-benzamide(compound A2) Step A: (R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylaminetrifluoroacetic acid salt

(2-Oxo-2lambda*4*-[1,2]oxathiolan-4-yl)-carbamic acid tert-butyl ester(prepared in 3 steps from L-cystine according to J. Org. Chem. 1981, 46,5408-5413) (345 mg) was dissolved in dichloromethane (7.8 ml) andtreated with trifluoroacetic acid (0.36 ml). The reaction mixture wasstirred at room temperature overnight and the solvent removed in vacuoto afford (R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylamine(trifluoroacetic acid salt), which was used directly in the next step.LCMS (Method E) 0.20 min, M+H 122.

Step B:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-2lambda*4*-[1,2]oxathiolan-4-yl)-benzamide

Oxalyl chloride (0.027 ml) was added to a solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (100 mg) (prepared according to WO 2009/080250) in dichloromethane(1.2 ml). After addition of two drops of N,N-dimethylformamide (“DMF”)the reaction mixture was stirred at ambient temperature for 18 hours.The reaction mixture was concentrated to give the acid chloride as ayellow solid, which was used in the next step without furtherpurification.

To a solution of the acid chloride in dichloromethane were addedtriethylamine (0.074 mL) followed by(R)-2-Oxo-2lambda*4*-[1,2]oxathiolan-4-ylamine (trifluoroacetic acidsalt) (59 mg). The reaction mixture was then stirred at room temperaturefor 24 hours. The reaction was quenched by adding water and the mixtureextracted with ethyl acetate. The combined organic layers were washedwith brine, dried (Na₂SO₄) and evaporated. Purification using reversephase chromatography afforded 16 mg of a first mixture of 2diastereomers as an oil, followed by 21 mg of a second mixture of 2other diastereomers as an oil. Fraction 1: LCMS (Method F) 2.04 min, M−H519/521. ¹H-NMR (CDCl₃, 400 MHz): 7.56-7.47 (m, 4H), 7.46-7.42 (m, 1H),7.41-7.34 (m, 1H), 6.24-6.04 (m, 1H), 5.23-5.12 (m, 1H), 4.99 (dd, 1H),4.75 (dd, 1H), 4.08 (d, 1H), 3.70 (d, 1H), 3.34 (d, 1H), 3.09 (d, 1H,J=6.6 Hz), 2.50 (s, 3H). Fraction 2: LCMS (Method) min, M−H 519/521.¹H-NMR (CDCl₃, 400 MHz): 7.58-7.39 (m, 6H), 5.48-5.37 (m, 1H), 4.88 (d,1H), 4.62 (d, 1H), 4.08 (d, 1H), 3.70 (d, 1H), 3.63-3.54 (m, 1H), 3.31(d, 1H), 2.46 (s, 3H).

EXAMPLE 94-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-(2-ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-2-methl-benzamide(compound D1) Step A:N-(3-Benzyloxy-2-hydroxy-propyl)-N-ethyl-methanesulfonamide

Triethylamine (0.043 ml, 0.1 equiv) was added to a mixture ofN-ethylmethanesulfonamide (413 mg, 1.1 equiv) and2-benzyloxymethyloxirane (500 mg, 3.04 mmol) prepared according to (J.Am. Chem. Soc., 1996, 118, 7094-7100) in anhydrous dioxane (1 ml). Thereaction mixture was then heated to 50° C. overnight. As the reactionwas not complete, it was heated to 100° C. for another 5 hours (reactioncomplete according to TLC). The volatiles were then removed in vacuo.Flash chromatography eluting with cyclohexane/Ethyl acetate (6/4 then1/1) afforded 836 mg (2.91 mmol, 96%). LCMS (Method E) 1.44 min, M+H288. ¹H-NMR (CDCl₃, 400 MHz): 7.43-7.27 (m, 5H), 4.57 (s, 2H), 4.11-3.90(m, 1H), 3.62-3.44 (m, 2H), 3.43-3.20 (m, 4H), 2.90 (s, 3H), 1.14-1.33(m, 3H).

Step B: 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide

Benzenesulfonyl chloride (0.41 ml, 1.1 equiv) was added to a solution ofN-(3-Benzyloxy-2-hydroxy-propyl)-N-ethyl-methanesulfonamide (836 mg,2.91 mmol) in pyridine (5.8 ml). The reaction mixture was then heated to50° C. for 24 hours. Ethyl acetate was added and a precipitate(pyridinium hydrochloride salt) formed. It was filtered and the residuewas diluted in ethyl acetate. The organic phase was then washed with 1Maqueous HCl, water, CuSO₄ aqueous solution and NaHCO₃ saturated aqueoussolution. The organic phase was then dried (Na₂SO₄) and evaporated.

To a solution of the aforementioned residue (2.61 mmol) in anhydroustetrahydrofuran at −78° C. was added n-BuLi (5.4 mL, 2.5 equiv). Thereaction mixture was then allowed to warm up to 0° C. and stirred atthis temperature for 2 hours. It was quenched by addition of saturatedaqueous NH₄Cl. The reaction mixture was then extracted with ethylacetate. The combined organic phases were washed with brine, dried(Na₂SO₄) and evaporated. Flash chromatography eluting withcyclohexane/Ethyl acetate (7/3) afforded 274 mg (1.017 mmol, 40%). LCMS(Method E) 1.59 min, M+H 270. ¹H-NMR (CDCl₃, 400 MHz): 7.40-7.27 (m,5H), 4.60-4.45 (m, 2H), 3.54 (dd, 2H), 3.37-3.20 (m, 2H), 3.17-2.85 (m,5H), 1.22 (t, 3H).

Step C: (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol

A mixture of 4-Benzyloxymethyl-2-ethyl-isothiazolidine 1,1-dioxide (254mg) and Pd/C (108 mg, 0.1 equiv) in methanol was purged with H₂ and leftto stir under an H₂ atmosphere for 24 h. As LCMS indicated completion,the reaction mixture was filtered through a pad of silica (rinsing withMeOH). The filtrate was evaporated and 162 mg of the expected alcoholwere obtained. It was pure enough to be used as such in the next step.LCMS (Method E) 0.25 min, M+H 170. ¹H-NMR (CDCl₃, 400 MHz): 3.8-3.70 (m,2H), 3.39-3.25 (m, 2H), 3.20-3.01 (m, 4H), 2.94-2.78 (m, 1H), 1.24 (t,3H).

Step D:2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3-dione

To a stirred solution of phthalimide (133 mg, 1 equiv) intetrahydrofuran (4.5 ml) was added triphenylphosphine (237 mg, 1 equiv)and (2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methanol (0.905mmol). This solution was cooled down to 0° C. for the dropwise additionof diisopropylazodicarboxylate (0.18 ml, 1 equiv). The reaction mixturewas stirred at room temperature over the weekend. It was thenconcentrated, and stirred in diethyl ether for 5 hours. Volatiles wereremoved in vacuo. Flash chromatography eluting with cyclohexane/ethylacetate (7/3) afforded 261 mg (0.85 mmol, 94%). LCMS (Method E) 1.40min, M+H 309. ¹H-NMR (CDCl₃, 400 MHz): 7.93-7.84 (m, 2H), 7.83-7.72 (m,2H), 3.89 (dd, 2H), 3.41-3.23 (m, 2H), 3.17-2.98 (m, 5H), 1.22 (t, 3H).

Step E: C-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methylamine

To a solution of2-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-isoindole-1,3-dione(261 mg, 0.85 mmol) in EtOH (4 ml) was added hydrazine monohydrate(0.165 ml, 4 equiv). The reaction mixture was then refluxed overnightand a white gum formed. The reaction mixture was filtered (rinsingseveral times with EtOH) and the filtrate was evaporated to afford 81 mgof the expected amine contaminated by 10% of2,3-Dihydro-phthalazine-1,4-dione. It was used as such in the next step.

¹H-NMR (MeOD, 400 MHz): 3.52-3.36 (m, 2H), 3.20-2.97 (m, 4H), 2.92-2.83(m, 2H), 2.83-2.69 (m, 1H), 1.26 (t, 3H).

Step F:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-(2-ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-ylmethyl)-2-methyl-benzamide

Oxalyl chloride (0.027 ml) was added to a solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (100 mg) (prepared according to WO 2009/080250) in dichloromethane(1.2 ml). After addition of two drops of N,N-dimethylformamide (“DMF”)the reaction mixture was stirred at ambient temperature for 18 hours.The reaction mixture was concentrated to give the acid chloride as ayellow solid, which was used in the next step without furtherpurification.

To a solution of the acid chloride in dichloromethane were addedtriethylamine (0.037 ml) followed by(C-(2-Ethyl-1,1-dioxo-1lambda*6*-isothiazolidin-4-yl)-methylamine (45mg). The reaction mixture was then stirred at room temperature for 24hours. The reaction was quenched by adding water and the mixtureextracted with ethyl acetate. The combined organic layers were washedwith brine, dried (Na₂SO₄) and evaporated. Purification using reversephase chromatography afforded 18 mg of a mixture of two diastereomers asan oil. LCMS (Method D) 2.21 min, M+H 578/580. ¹H-NMR (CDCl₃, 400 MHz):7.56-7.49 (m, 4H), 7.47-7.40 (m, 2H), 6.23-6.32 (m, 1H), 4.09 (d, 1H),3.74-3.53 (m, 3H), 3.46-3.27 (m, 2H), 3.17-3.00 (m, 5H), 2.47 (s, 3H),1.23 (t, 3H).

EXAMPLE 104-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-(2-ethyl-isoxazolidin-4-yl)-2-methyl-benzamide(compound A3) Step A:2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoicacid methyl ester

Triethylamine (0.11 ml, 0.1 equiv) was added to a mixture ofN-hydroxyphthalimide (1.13 g, 6.9 mmol) and2-Bromomethyl-1-(2-nitro-benzenesulfonyl)-aziridine (7.6 mmol, 1.1equiv) (prepared according to Org. Biomol. Chem. 2008, 6, 1902-1904) inanhydrous dioxane (4.5 ml). The reaction mixture was then heated to 50°C. over the weekend. Then methanol (2.5 ml) and triethylamine (1.1 ml, 1equiv) were added and the reaction mixture was heated at 50° C. foranother 4 hours. Volatiles were then removed in vacuo. Flashchromatography eluting with cyclohexane/ethyl acetate (1/1 then 3/7)afforded 2.46 g of the title compound (5.67 mmol, 74%). LCMS (Method E)1.55 min, M+H 435. ¹H-NMR (CDCl₃, 400 MHz): 8.21-8.11 (m, 1H), 8.00 (d,1H), 7.90-7.67 (m, 3H), 7.63-7.56 (m, 1H), 7.55-7.46 (m, 1H), 7.41 (d,1H), 6.87-6.73 (m, 1H), 4.77-4.67 (m, 1H), 4.22-3.95 (m, 5H), 3.93-3.75(m, 2H).

Step B: 2-(4-Amino-isoxazolidine-2-carbonyl)-benzoic acid methyl ester

A solution of2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoicacid methyl ester (200 mg, 0.46 mmol) and PhSH (0.035 ml, 1.1 equiv) inacetonitrile (2.3 ml) under argon at rt was treated with K₂CO₃ (95 mg,1.5 equiv). The reaction mixture turned bright yellow. The reaction wasleft to stir overnight. As TLC indicated complete consumption ofstarting material, volatiles were removed in vacuo. Flash columnchromatography eluting with dichloromethane:methanol (9/1) afforded 85mg of the expected amine (0.34 mmol, 74%). LCMS (Method E) 0.55 and 1.41min, M+H 251. ¹H-NMR (CDCl₃, 400 MHz): 7.95 (d, 1H), 7.63-7.52 (m, 1H),7.51-7.36 (m, 2H), 4.17-3.92 (m, 3H), 3.87 (s, 3H), 3.80-3.55 (m, 2H),2.04-1.75 (m, 2H).

Step C:2-(4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazolidine-2-carbonyl)-benzoicacid methyl ester

Oxalyl chloride (0.037 ml) was added to a solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (135 mg) (prepared according to WO 2009/080250) in dichloromethane(1.6 ml). After addition of two drops of N,N-dimethylformamide (“DMF”)the reaction mixture was stirred at ambient temperature for 18 hours.The reaction mixture was concentrated to give the acid chloride as ayellow solid, which was used in the next step without furtherpurification.

To a solution of the acid chloride in dichloromethane (3.2 ml) wereadded triethylamine (0.090 ml) followed by2-(4-Amino-isoxazolidine-2-carbonyl)-benzoic acid methyl ester (85 mg).The reaction mixture was then stirred at room temperature for 24 hours.The reaction was quenched by adding water and the mixture extracted withethyl acetate. The combined organic layers were washed with brine, dried(Na₂SO₄) and evaporated. Flash column chromatography eluting withcyclohexane/EtOAc (1/1) afforded 187 mg the expected amine as a mixtureof (separable) diastereomers (0.29 mmol, 90%). LCMS (Method F) 2.11 and2.15 min, M−H 648/650. ¹H-NMR (CDCl₃, 400 MHz): 7.96 (d, 1H), 7.81-7.68(m, 1H), 7.68-7.60 (m, 1H), 7.60-7.42 (m, 8H), 5.39-5.42 (m, 1H),4.57-4.43 (m, 1H), 4.31-4.24 (m, 1H), 4.08 (d, 1H), 4.01-3.88 (m, 1H),3.87-3.78 (m, 1H), 3.72 (d, 1H), 3.62 (s, 3H), 2.52 (s, 3H).

Step D: 4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic acidtert-butyl ester

2-[4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carbonyl]-benzoicacid methyl ester (2.67 g, 6.14 mmol) was suspended in 20 ml 2M aqueousHCl and the mixture was refluxed for 48 hours. It was then filtered andthe solids were washed with water. The filtrate was then evaporated anddried under vacuum. The residue was triturated in i-PrOH. The solid wasfiltered and the filtrate evaporated. This filtrate (177 mg) was used assuch without further purification. LCMS (Method E) 0.87 and 0.95 min,M+H 274.

A suspension of the aforementioned residue in MeCN (30 ml) was treatedwith Et₃N (3.62 ml, 4.2 equiv) and the reaction mixture turned clear.Then Boc₂O (2.01 g, 1.5 equiv) was added and the reaction mixture wasleft to stir under argon at rt for 36 hours. It was quenched by additionof water and extracted with EtOAc. The combined organic extracts weredried (Na₂SO₄) and evaporated. Flash chromatography eluting withcyclohexane/ethyl acetate (6/4) afforded 1.69 g (4.52 mmol, 74%). LCMS(Method D) 1.66 min, M+Na 396. ¹H-NMR (CDCl₃, 400 MHz): 8.18-8.13 (m,1H), 7.95-7.88 (m, 1H), 8.85-7.74 (m, 2H), 5.78 (d, 1H), 4.54-4.42 (m,1H), 3.95 (dd, 1H), 3.91-3.80 (m, 2H), 3.49 (dd, 1H), 1.49 (s, 9H).

Step E: 4-Amino-isoxazolidine-2-carboxylic acid tert-butyl ester

A solution of4-(2-Nitro-benzenesulfonylamino)-isoxazolidine-2-carboxylic acidtert-butyl ester (694 mg, 1.86 mmol) and PhSH (0.142 ml, 1.1 equiv) inMeCN (10 ml) under argon at room temperature was treated with K₂CO₃ (386mg, 1.5 equiv). The reaction mixture turned bright yellow. The reactionwas left to stir overnight. As TLC indicated complete consumption ofstarting material, volatiles were removed in vacuo. Flash columnchromatography eluting with dichloromethane:methanol (10/0 then 9/1)afforded 336 mg of the title amine (1.8 mmol, 96%). ¹H-NMR (CDCl₃, 400MHz): 4.03-3.92 (m, 3H), 3.89-3.76 (m, 1H), 3.70 (dd, 1H), 3.37 (dd,1H), 1.51 (s, 9H).

Step F:4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazlidine-2-carboxylicacid tert-buty ester

Oxalyl chloride (0.20 ml) was added to a solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (749 mg) (prepared according to WO 2009/080250) in dichloromethane(9 ml). After addition of two drops of N,N-dimethylformamide (“DMF”) thereaction mixture was stirred at ambient temperature for 18 hours. Thereaction mixture was concentrated to give the acid chloride as a yellowsolid, which was used in the next step without further purification.

To a solution of the acid chloride in dichloromethane (18 ml) were addedtriethylamine (0.30 ml) followed by 4-Amino-isoxazolidine-2-carboxylicacid tert-butyl ester (336 mg). The reaction mixture was then stirred atroom temperature for 24 hours. The reaction was quenched by adding waterand the mixture extracted with ethyl acetate. The combined organiclayers were washed with brine, dried (Na₂SO₄) and evaporated. Flashcolumn chromatography eluting with cyclohexane/EtOAc (1/1) afforded 197mg the expected amine as a mixture of diastereomers.

¹H-NMR (CDCl₃, 400 MHz): 7.60-7.48 (m, 4H), 7.47-7.36 (m, 2H), 6.23.6.15(m, 1H), 5.08-4.98 (m, 1H), 4.20-3.94 (m, 4H), 3.70 (d, 1H), 3.66-3.58(m, 1H), 2.48 (s, 3H), 1.50 (s, 9H).

Step G:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamidetrifluoroacetic acid salt

To a solution of4-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-isoxazlidine-2-carboxylicacid tert-butyl ester (198 mg, 0.34 mmol) in dichloromethane (1.7 ml)was added trifluoroacetic acid (0.15 ml, 5 equiv). The reaction mixtureimmediately turned black. The reaction mixture was left to stir for 6hours. Volatiles were then removed in vacuo. Flash column chromatographyeluting with ethyl acetate/methanol (10/0 to 9/1) afforded 92 mg of theexpected compound as a mixture of diastereomers. LCMS (Method E) 1.93min, M+H 488/490.

Step H:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-(2-ethyl-isoxazolidin-4-yl)-2-methyl-benzamide

Crude4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-isoxazolidin-4-yl-2-methyl-benzamidetrifluoroacetic acid salt (0.16 mmol) was dissolved in MeOH (0.8 ml).Then acetaldehyde (0.090 ml, 10 equiv) was added at 0° C. under an argonatmosphere. After stirring for 1 hour at 0° C., NaBH₃CN (20 mg, 2 equiv)was added. The reaction mixture was left to stir over the weekend. Itwas then evaporated. Flash column chromatography eluting with ethylacetate/methanol (10/0 to 9/1) afforded 7.5 mg of the expected compoundas a mixture of diastereomers. LCMS (Method E) 2.02 min, M+H 516/518.¹H-NMR (MeOD, 400 MHz): 7.70-7.53 (m, 5H), 7.52-7.37 (m, 1H), 4.92-4.85(m, 1H), 4.40-4.22 (m, 2H), 4.00 (d, 1H), 3.83-3.62 (m, 1H), 3.29-2.52(m, 4H), 2.43 (s, 3H), 1.16 (t, 3H).

EXAMPLE 114-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[(2-oxido-1,3,2-dioxathiolan-2-ium-4-yl)methyl]benzamide(Compound F5) Step A: Preparation of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,3-dihydroxy-propyl)-2-methylbenzamide

A solution of 10% Sulfuric acid (0.1 ml) and4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,2-dimethyl-[1,3]dioxolane-4-ylmethyl)-2-methylbenzamide(1 g, 1.9 mmol) in methanol (50 ml) was stirred at 70° C. for 4 hours.The solvent was evaporated and the crude mixture was diluted with ethylacetate (100 ml), washed with a saturated aqueous solution of sodiumhydrogencarbonate (20 ml×2) and then with water (50 ml). The combinedorganic extracts were dried over sodium sulfate and concentrated invacuo to give the title compound as a solid (0.7 g). M.p. 98-98° C. LCMS(Method G) 3.65 min, MH⁺ 491. ¹HNMR (CDCl₃, 400 MHz): 7.37-7.49 (m, 6H),6.59 (t, 1H), 4.12 (d, 1H), 3.88 (m, 1H), 3.67 (d, 1H), 3.60 (m, 4H),2.41 (s, 3H).

Step B: Preparation of4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-[(2-oxido-1,3,2-dioxathiolan-2-ium-4-yl)methyl]benzamide

A solution of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(2,3-dihydroxy-propyl)-2-methylbenzamide(100 mg, 0.2 mmol) in dichloromethane (10 ml) was cooled to 0° C.,treated with Pyridine (0.08 ml, 1.0 mmol) and thionyl chloride (0.03,0.4 mmol), and stirred for 6 hours. The mixture was diluted withdichloromethane (50 ml), neutralized with 2N hydrochloric acid andwashed with water (50 ml). The organic layer was separated, dried oversodium sulfate and concentrated to give the title compound (65 mg) as amixture of diastereoisomers. Purification by preparative HPLC gave thediastereoisomer 1 (28 mg) and the diastereoisomer 2 (18 mg);

Diastereoisomer 1: LCMS (Method G) 4.07 min, MH⁺536. ¹HNMR (CDCl₃, 400MHz): 7.37-7.50 (m, 6H), 6.26 (m, 1H), 5.16 (m, 1H), 4.79 (m, 1H), 4.32(m, 1H), 4.10 (m, 2H), 3.71 (m, 2H), 2.45 (s, 3H).

Diastereoisomer 2: LCMS (Method G) 4.17 min, MH⁺536. ¹HNMR (CDCl₃, 400MHz): 7.47-7.52 (m, 5H), 7.42 (s, 1H), 6.58 (m, 1H), 4.88 (m, 1H), 4.59(m, 1H), 4.47 (m, 1H), 4.10 (m, 2H), 3.75 (m, 2H), 2.45 (s, 3H).

EXAMPLE 12N-(2-Benzyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide(compound F1) Step A: (2-Benzyl-isoxazolidin-5-ylmethyl)-carbamic acidtert-butyl ester

Following the procedure described in Tetrahedron 55, 1999, 4685-4698,N-BOC-allylamine (2 g) was dissolved in toluene (130 ml) and ethanol (45ml) then benzylhydroxylamine hydrochloride (3.05 g), paraformaldehyde(3.16 g) and triethylamine (1.93 g) were added. The reaction mixture wasallowed to stir at room temperature for 24 hours, then the solvent wasevaporated in vacuo. The resulting residue was diluted in ethyl acetateand the hydrochloride salt of triethylamine was filtered off. Thefiltrate was concentrated in vacuo and the residue purified by columnchromatography (ethyl acetate/cyclohexane 1:1) to afford the titlecompound as a colorless oil (4.37 g). LCMS (Method F) 1.53 min, M+H 293.

Step B: C-(2-Benzyl-isoxazolidin-5-yl)-methylamine

A solution of (2-benzyl-isoxazolidin-5-ylmethyl)-carbamic acidtert-butyl ester (Step A, 0.5 g) in dichloromethane (10 ml) was treatedwith trifluoroacetic acid (1.95 g). The solution was stirred at roomtemperature for 4 hours then concentrated in vacuo to afford the crudetitle product, which was used directly for the next step. LCMS (MethodF) 0.20 min, M+H 194.

Step C:N-(2-Benzyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide

To a stirred solution of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (1.75 g) (prepared according to WO 2009/080250) in acetonitrile (35ml) and triethylamine (2.04 ml) were added under nitrogen atmosphereTBTU (1.61 g), AZA.HOBT (0.68 g) andC-(2-Benzyl-isoxazolidin-5-yl)-methylamine (Step B, 1.61 g) were added.The resulting solution was stirred at room temperature for 4 hours, thenquenched by addition of aqueous saturated ammonium chloride solution.The mixture was then extracted with ethyl acetate, dried over sodiumsulfate, filtered then concentrated in vacuo. The residue purified bycolumn chromatography (ethyl acetate/cyclohexane 1:1) to afford thetitle compound as a white solid (60 mg, (mixture of diasteroisomers).LCMS (Method F) 2.20 min, M+H 636/638.

The following compound was prepared following a similar method to thatdescribed in Example 12:N-(2-methyl-isoxazolidin-5-ylmethyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide(compound F2).

EXAMPLE 134-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[3-oxo-2-ethyl-isoxazolidin-5-ylmethyl]-benzamide(compound F3) Step A: (3-Bromo-4,5-dihydro-isoxazol-5-ylmethyl)-carbamicacid tert-butyl ester

Following the procedure described in Tetrahedron 46, 1990, 1975-1986,N-BOC-allylamine (1.8 g) was dissolved in ethyl acetate and treated withsodium hydrogenocarbonate (4.38 g) and dibromoformaldoxime (2.55 g). Thereaction mixture was stirred at room temperature for 4 hours, thenpoured into water, extracted with ethyl acetate, the organic layer wasdried over sodium sulfate and the solvent removed in vacuo. The titlecrude product was thus obtained as a colorless oil (3.16 g). LCMS(Method F) 1.48 min, M+H 179/181 (M-BOC).

Step B: (3-Oxo-isoxazolidin-5-ylmethyl)-carbamic acid tert-butyl ester

Following the procedure described in Tetrahedron 46, 1990, 1975-1986,the crude product obtained in Step A (1.5 g) was dissolved in THF andtreated with 1N aqueous sodium hydroxide (150 ml) in the presence oftetrabutyl ammonium sulfate (0.54 g). After 24 hours stirring at roomtemperature, aqueous sodium hydroxide (1N, 50 ml) was added again andthe reaction mixture stirred for another 48 hours at 60° C. The reactionmixture was then cooled to room temperature, extracted with diethylether and the pH of the aqueous layer adjusted to 1 by addition of 2NHCL. The aqueous layer was then extracted with ethyl acetate, theorganic layers were combined, dried over sodium sulfate and the solventsremoved in vacuo. Column chromatography (ethyl acetate/cyclohexane 1:1)afforded the title product as a white solid (220 mg). LCMS (Method F)1.06 min, M+H 217. ¹HNMR (CDCl₃, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H),3.40 (m, 2H), 2.75 (dd, 1H), 2.60 (dd, 1H), 1.50 (s, 9H).

Step C: (2-Ethyl-3-oxo-isoxazolidin-5-ylmethyl)-carbamic acid tert-butylester

The product obtained in Step B (0.1 g) was alkylated with bromoethane asdescribed in Example 4, step A to afford the O-alkylated product (18mg), ¹HNMR (CDCl₃, 400 MHz): 4.90 (m, 1H), 4.70 (m, 1H), 4.2 (q, 2H),3.35 (m, 2H), 3.00 (dd, 1H), 2.75 (dd, 1H), 1.50 (s, 9H), 1.35 (t, 3H);and the title N-alkylated product (63 mg). ¹HNMR (CDCl₃, 400 MHz): 4.85(m, 1H), 4.55 (m, 1H), 3.60 (m, 2H), 3.40 (m, 2H), 2.80 (dd, 1H), 2.60(dd, 1H), 1.50 (s, 9H), 1.20 (t, 3H).

Step D: 5-Aminomethyl-2-ethyl-isoxazolidin-3-one

A solution of the product obtained in Step C in dichloromethane (2 ml)was treated with trifluoroacetic acid (0.15 g). The solution was stirredat room temperature for 4 hours then concentrated in vacuo to afford thecrude title product, which was used directly for the next step. LCMS(Method F) 0.18 min, M+H 145.

Step E:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[3-oxo-2-ethyl-isoxazolidin-5-ylmethyl]-benzamide

4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (0.3 g) (prepared according to WO 2009/080250) was coupled with theamine obtained in Step D (0.12 g) as described in Example 12, Step C toafford the title product as a beige solid (62 mg, mixture ofdiasteroisomers). LCMS (Method F) 2.02 min, M+H 542/544.

The following compound was prepared following a similar method to thatdescribed in Example 13:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-[3-oxo-2-(1,1,1-trifluoroethyl)-isoxazolidin-5-ylmethyl]-benzamide(compound F4).

EXAMPLE 144-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[2-(4-methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-2-methyl-benzamide (compound F6)Step A: 2-Nitrilo-ethanesulfonic acid (4-methoxy-phenyl)-amid

To a solution of para-anisidine (1.95 g) in acetonitrile (25 ml) at 15°C. under argon atmosphere was added pyridine (1.25 g), thencyanomethanesulfonyl chloride (2 g) and the reaction mixture was stirredat room temperature for 1 hour. The reaction mixture was poured into 50ml water and the pH was made basic by addition of 1N aqueous sodiumhydroxide. The aqueous layer was extracted with ethyl acetate, thecombined organic layers were dried over sodium sulfate, thenconcentrated in vacuo. Column chromatography (ethyl acetate/cyclohexane1:1) afforded the title product as an orange solid (590 mg). ¹HNMR(CDCl₃, 400 MHz): 7.30 (d, 2H), 6.95 (d, 2H), 6.70 (m, 1H), 3.95 (s,2H), 3.85 (s, 3H).

Step B:2-(4-Methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidine-5-carbonitrile

To a solution of the compound obtained in Step A (0.59 g) indimethylformamide (40 ml) was added potassium carbonate (1.1 g). Then, asolution of 1,2-dibromoethane (0.59 g) in dimethylformamide (25 ml) wasadded dropwise at 55° C. The reaction mixture was then stirred at 55° C.for 2 hours, cooled to room temperature, poured into 15 ml water, andaqueous 2N hydrochloric acid was added to acidic pH. The aqueous layerwas then extracted with dichloromethane, the combined organic layerswashed two times with 2% aqueous hydrochloric acid, dried over sodiumsulfate and concentrated in vacuo. Column chromatography (ethylacetate/cyclohexane 7:3) afforded the title product as a beige solid(310 mg). ¹HNMR (CDCl₃, 400 MHz): 7.30 (d, 2H), 6.90 (d, 2H), 4.25 (m,1H), (m, 1H), 3.70-3.90 (m, 5H), 2.95 (m, 1H), 2.80 (m, 1H).

Step C:[2-(4-Methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-carbamicacid tert-butyl ester

To a solution at 0° C. of the product obtained in Step B (500 mg) inmethanol (15 ml) were added di-tert-butyldicarbonate (807 mg) andnickel(II) chloride hexahydrate (90 mg). Sodium borohydride (490 mg) wasadded portionwise. The reaction mixture was allowed to stir at roomtemperature for 24 hours. Diethylenetriamine (190 mg) was added, thereaction mixture was stirred for 30 min at room temperature then thesolvent was removed in vacuo. The purple solid residue was diluted inethyl acetate then washed with aqueous saturated hydrogen bicarbonate.The aqueous layer was extracted with ethyl acetate, the combined organiclayers were dried over sodium sulfate and concentrated in vacuo.Purification using the Combi Flash200 afforded the title product as animpure brown oil (80 mg), which was used directly in the next step.

Step D:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[2-(4-methoxy-phenyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-2-methyl-benzamide

The compound obtained in Step C (94 mg) was deprotected and coupled with4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (0.125 g) (prepared according to WO 2009/080250) as described inExample 4, Steps B and C to afford the title compound as a brown solid(65 mg). LCMS (Method F) 2.02 min, M−H 654/655.

The following compounds were prepared following a similar method to thatdescribed in Example 14:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N-[2-(2,2,2-trifluoroethyl)-1,1-dioxo-1lambda*6*-isothiazolidin-5-ylmethyl]-2-methyl-benzamide(Compound F7).

EXAMPLE 15 Preparation of enantiomerically pure isomers of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide

4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (prepared as described in WO 2009/080250) was separated throughchiral phase preparative HPLC (Column: CHIRALPAK® AD-H 5 μm; MobilePhase: 80/20 Carbon Dioxide/Ethanol+1% Diethylamine; Flow Rate: 120ml/min; Detection: 270 nm; Temperature: 25° C.; Outlet Pressure: 150bars) to afford4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (a_(D) +51.43°) and4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (α_(D) −51.90°).

Amide coupling with (R)-4-Amino-2-ethyl-isoxazolidin-3-one and(S)-4-Amino-2-ethyl-isoxazolidin-3-one using the procedure described inExample 12, Step C afforded the 4 isomers of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide:

4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound G1) Chiral HPLC (method H) RT 21.30 min, purity 97%.

4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound G2): Chiral HPLC (method H) RT 19.79, purity 82%.

4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound G3): Chiral HPLC (method H) RT 21.11, purity 91%.

4-[5-(3,5-dichloro-phenyl)-5-(R)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((S)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide(Compound G4): Chiral HPLC (method H) RT 17.07, purity 95%.

EXAMPLE 164-[(S)-5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-N—[(R)-2-(2,2-difluoro-ethyl)-3-oxo-isoxazolidin-4-yl]-2-methyl-benzamide(compound G6)

Step A: [(R)-2-(2,2-Difluoro-ethyl)-3-oxo-isoxazolidin-4-yl]-carbamicacid tert-butyl ester

As described in Example 4, Step A, (3-oxo-isoxazolidin-4-yl)-carbamicacid tert-butyl ester (0.30 g) was alkylated with 2,2-difluoroethyltrifluoromethanesulfonate (0.35 g). to afford the title product as awhite solid (138 mg); ¹H-NMR (CDCl₃, 400 MHz): 6.05 (tt, 1H), 5.10 (m,1H), 4.90 (m, 1H), 4.35 (dt, 2H), 4.20 (dd, 1H), 1.50 (s, 9H); alongwith the O-alkylated product (179 mg): ¹H-NMR (CDCl₃, 400 MHz): 5.95(tt, 1H), 4.80 (m, 1H), 4.60 (m, 1H), 3.80-4.10 (m, 3H), 1.50 (s, 9H).

Step B: (R)-4-Amino-2-(2,2-difluoroethyl)-isoxazolidin-3-one

The BOC protecting group was removed as described in Example 4, Step Bto afford (R)-4-amino-2-(2,2-difluoroethyl)-isoxazolidin-3-one(trifluoroacetic acid salt), which was used directly in the next step.

Step C:4-[5-(3,5-Dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2,2-difluoroethyl)-3-oxo-isoxazolidin-4-yl)-benzamide

Amide coupling was performed using4-[5-(3,5-dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (0.27 g, prepared according to Example 15) as described in Example12, step C. The title compound was obtained as a white solid (158 mg).M.p. 77-78° C.; LCMS (Method F) 2.09 min, M+H 564/566.

The following compound was prepared following a similar method to thatdescribed in Example 16:4-[5-(3,5-Dichloro-phenyl)-5-(S)-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-(2,2-difluoroethyl)-3-oxo-isoxazolidin-4-yl)-benzamide(compound G5).

EXAMPLE 176-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotinamide(compound C6) Step A: 5-Bromo-2-iodo-4-methyl-pyridine

To a solution of 2,5-dibromo-4-methylpyridine (2 g) in acetonitrile (40ml) at room temperature under argon were added sodium iodide (4.8 g)then acetyl chloride (0.94 g). After 3 hours stirring at roomtemperature the white solid formed was filtered off and the filtrate wasneutralized with aqueous saturated solution of sodiumhydrogenocarbonate. The organic phase was dried over sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatography(ethyl acetate/cyclohexane) to afford the title product as a brown solid(2.04 g). ¹H-NMR (CDCl₃, 400 MHz): 8.40 (s, 1H), 7.60 (s, 1H), 2.30 (s,3H),

Step B: 5-Bromo-4-methyl-pyridine-2-carbaldehyde

In an oven-dried flask the compound obtained in Step A (4.67 g) wasdissolved in tetrahydrofuran (22 ml). The solution was cooled to −15°C., then isopropyl magnesium bromide (17.2 ml, 15% solution in THF) wasadded dropwise at a rate to keep the internal temperature between −15°C. to −10° C. The reaction was stirred at this temperature for 1 hour,then anhydrous dimethylformamide (1.8 ml) was added at a rate to keepthe internal temperature below 0° C. The reaction was stirred at thistemperature for 1 hour, then poured into water and extracted withdiethyl ether. The organic layer was dried over sodium sulfate andconcentrated in vacuo. The crude title aldehyde product (2.4 g, brownsolid) was used as such in the next step.

Step C: 5-Bromo-4-methyl-pyridine-2-carbaldehyde oxime

To a solution of the compound obtained in Step B (3.1 g) in EtOH (47.5ml) and water (23 ml) were added hydroxylamine hydrochloride (1.4 g) andsodium acetate (1.9 g). The reaction was stirred for 15 min at roomtemperature. The white solid was filtered off and the solutionconcentrated in vacuo to afford the crude title product (2.2 g, whitesolid), which was used directly for the next step. LCMS (Method F) 2.09min, M+H 564/566.

Step D:5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-pyridine

To a solution of the compound obtained in Step C (2.2 g) indimethylformamide (24 ml) was added N-chlorosuccinimide (1.4 g) in threeportions at room temperature under argon. The reaction mixture wasallowed to stir overnight at room temperature then a solution of1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.7 g, prepared asdescribed in WO 2009/080250) in DMF (6 ml) was added followed bytriethylamine (1.43 ml) in DMF (14 ml). The reaction stirred at roomtemperature for 1 hour then poured into ice water. A white solidprecipitated, which was filtered, washed with water and dried undervacuum to give the title product (4.1 g). ¹H-NMR (CDCl₃, 400 MHz): 8.60(s, 1H), 7.90 (s, 1H), 7.50 (s, 2H), 7.40 (s, 1H), 4.20 (d, 1H), 3.85(d, 1H), 2.45 (s, 3H),

Step E:6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-nicotinicacid

In a 300 ml flask were charged n-butanol (90 ml), palladium acetate (38mg) and n-butyl-diadamantylphosphine (184 mg). Then,tetramethylendiamine (1.93 ml) and5-bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-pyridine(7.5 g, obtained as described in Step D) were added.

The reaction was performed under carbon monoxide at 15 bar at roomtemperature for 20 min. The reaction mixture was then diluted in tolueneand the suspension was filtered on Celite and washed with toluene. Thesolvent was removed under reduced pressure to obtain a red oil. Theresidue was purified by column chromatography (ethyl acetate,cyclohexane) to yield the butyl ester of the title product as a liquid(3.45 g). ¹H-NMR (CDCl₃, 400 MHz): 9.03 (s, 1H), 7.90 (s, 1H), 7.50 (s,2H), 7.40 (s, 1H), 4.35 (t, 2H), 4.25 (d, 1H), 3.90 (d, 1H), 2.55 (s,3H), 1.80 (q, 2H9, 1.50 (q, 2H), 1.00 (t, 3H). This ester was dissolvedin tetrahydrofuran (8 ml), and sodium hydroxide (0.58 g) in methanol (8ml) and water (16 ml) was added dropwise. The reaction mixture wasstirred at room temperature for 3 hours, diluted with ethyl acetate andacidified with 1N hydrochloric acid. The aqueous layer was extractedwith ethyl acetate and the combined organic layers were dried oversodium sulfate then concentrated in vacuo. The residue was triturated inheptane and filtered to obtain the title product as a beige solid (2 g).LCMS (Method F) 2.22 min, M+H 419/421.

Step F:6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotinamide

The title compound was obtained by coupling the carboxylic acid obtainedin Step E (0.15 g) with(R)-4-Amino-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-3-one (0.10 g,obtained as described in Example 3 for the preparation of compound B5)as described in Example 12, Step C. The title product was obtained as awhite solid (48 mg). M.p. 53-55° C. LCMS (Method F) 2.13 min, M+H583/585.

The following compound was prepared following a similar method to thatdescribed in Example 17:6-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-nicotinamide(compound C7).

Similarly, when this reaction was carried out to obtain2-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzamide(compound C8), it was possible to separate the two diastereoisomers byprecipitation after the purification by column chromatography. Theproduct obtained after column chromatography was thus stirred withdiethyl ether and a solid precipitated out of the solution. The solid(enriched in one diastereomer) was analysed by chiral HPLC (method K):8.90 min (91.02%), 11.97 min (08.98%). The filtrate (enriched in theother diastereomer) was also analysed by chiral HPLC (method K): 8.66min (17.50%), 11.02 min (69.38%).

Similarly, when this reaction was carried out to obtain4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—[(R)-3-oxo-2-(2,2,2-trifluoro-ethyl)-isoxazolidin-4-yl]-benzamide(compound C9), it was possible to separate the two diastereoisomers byprecipitation after the purification by column chromatography. Theresidue was stirred with diethyl ether and a solid precipitated out ofthe solution. The solid (enriched in one diastereomer) was analysed bychiral HPLC (method K): 8.31 min (87.79%). The filtrate (enriched in theother diastereomer) was also analysed by chiral HPLC (method K): 8.28min (18.15%), 10.75 min (81.85%).

EXAMPLE 18 General Method for Preparing the Compounds of the Inventionin Parallel

To a solution of a benzoic acid of the formula (IIh) (20 μmol) inN,N-dimethylacetamide (“DMA”) (0.4 ml) was added successively a solutionof an amine of the formula (IIIh) (26 mol) in N,N-dimethylacetamide(“DMA”) (0.4 ml), diisopropylethylamine (Hunig's Base) (0.03 ml), and asolution of bis(2-oxo-3-oxazolidinyl)phosphonic chloride (“BOP-Cl”)(10.2 mg) in N,N-dimethylacetamide (“DMA”) (0.2 ml). The reactionmixture was stirred at 90° C. for 16 hours. The reaction mixture wasconcentrated and the crude mixture was redissolved inacetonitrile/N,N-dimethylacetamide (4:1) (0.8 ml) and purified by HPLC.This method was used to prepare a number of compounds (Compound Nos. H1to H26 of Table H) in parallel. The starting carboxylic acids used forthe preparation of compounds of Table H were obtained as described inExamples 19 to 31.

EXAMPLE 192-Methyl-4-[5-(3-trifluoromethoxy-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This compound was prepared following a similar route to that describedin Example 24.

EXAMPLE 206-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-nicotinicacid

This compound was prepared from 2,5-dibromo-6-methyl-pyridine followinga similar route to that described in Example 17, Steps A-E.

EXAMPLE 218-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-quinoline-5-carboxylicacid

The title product was prepared from 5-bromo-quinoline-8-carbaldehydeusing the same synthetic route described in Example 17, Steps C-E.

5-Bromo-quinoline-8-carbaldehyde was prepared as follows:

Step A: 5-Bromo-8-methyl-quinoline

A solution of 5-Bromo-2-methylaniline (7.44 g), glycerol (7.4 g),nitrobenzene (4.9 g) in 75% sulfuric acid (20 ml) was heated at 150° C.for 3 hrs. The solution was cooled to 0° C. then carefully neutralizedwith aqueous sodium hydroxide. The reaction mixture became a dark gumand was diluted with water and extracted three times with ethyl acetate.The combined organic layers were washed with saturated brine, then driedwith sodium sulphate and the solvent removed in vacuo. The crude productwas purified by column chromatography (dichloromethane) to afford thetitle compound as a solid (6 g). ¹H-NMR (CDCl₃, 400 MHz) 8.91 (m, 1H),8.51 (m, 1H), 7.7 (m, 1H), 7.50 (m, 1H), 7.4 (m, 1H), 2.72 (s, 3H).

Step B: 5-Bromo-8-dibromomethyl-quinoline

Radical dibromination was performed using standard method from thecompound obtained in Step A (4.4 g), N-bromo-succinimide (8.9 g) intetrachloromethane (200 ml) at reflux for 12 hours in the presence ofdibenzoyl peroxide (245 mg). At the end of the reaction, the succinimidewas filtered off, the solvent was removed in vacuo, and the crudeproduct used as such for the next step. ¹H-NMR (CDCl₃, 400 MHz) 8.90 (m,1H), 8.45 (dd, 1H), 8.15 (d, 1H), 8.10 (s, 1H), 7.80 (d, 1H), 7.45 (m,1H).

Step C: 5-Bromo-quinoline-8-carbaldehyde

Hydrolysis of the dibromo compound obtained using the method describedin Step B (9 g) was carried out in acetone (138 ml) and water (23 ml) inthe presence of silver nitrate (9.7 g) in the dark at room temperaturefor 5 hours. The silver salts were filtered off through a pad of Celite.The filtrate was diluted with ethyl acetate (150 ml), transferred to aseparatory funnel, then washed successively with saturated aqueoussodium bicarbonate (100 ml), water (3×50 ml), and brine (50 ml). Theorganic layer was dried over sodium sulphate filtered, and evaporatedunder reduced pressure to afford the title product (4.70 g) as a yellowsolid. ¹H-NMR (CDCl₃, 400 MHz) 11.4 (s, 1H, CHO) 9.05 (m, 1H), 8.61 (dd,1H), 8.15 (d, 1H), 8.0 (d, 1H), 7.60 (m, 1H)

EXAMPLE 224-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-pyridine-2-carboxylicacid

This compound was prepared from 5-formyl-pyridine-2-carboxylic acidmethyl ester using the standard synthesis described in WO 2009/080250.5-Formyl-pyridine-2-carboxylic acid methyl ester was synthesized byreductive formylation of 5-bromo-pyridine-2-carboxylic acid methyl esterusing the conditions described in Angewandte Chemie, InternationalEdition (2006), 45(1), 154-158.

EXAMPLE 232-Cyclopropyl-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This acid was prepared from the methyl ester of2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid (Example 27) as follows:

A solution of cyclopropyl boronic acid (0.67 g),2-bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid methyl ester (3 g) and Bis(triphenylphosphine)palladium(II)chloride (210 mg) were sequentially added to degassed toluene (38 ml).The reaction mixture was stirred for 30 min at room temperature then adegassed aqueous 2N solution of potassium phosphate (7 ml) was added andthe resulting mixture was heated at 110° C. overnight. The reactionmixture was filtered over Hyflo and the resulting solution wasconcentrated in vacuo to give a yellow oil, which was poured into ethylacetate. The organic phase was washed with water, dried over sodiumsulfate, and the solvents were evaporated in vacuo. The product was usedas such for the saponification step, as described in Example 17, Step Eto afford the title acid compound (2.5 g) as a yellow solid. LCMS(Method F) 2.15 min M−H 442/444.

EXAMPLE 242-Methyl-4-[5-(4-cyano-3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

Steps A-C: Preparation of2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile

Step A

To a solution of Bis(1,5-cyclooctadiene)dimethoxydiiridium (35 mg) inhexane (10 ml) under argon was added 4,4′-Di-tert-butyl-2,2′-bipyridine(110 mg). To this dark brown suspension was added pinacol diborane (2.23g) and the solution was stirred at room temperature for 5 min. To thissolution was added 2,6-Dichloro-benzonitrile (1 g) and the mixture washeated at 50° C. for 22 hours. The solution was then filtered on aCelite pad and the filtrate was concentrated. The residue was thendissolved with ethyl acetate and extracted with saturated ammoniumchloride. The organic layer was washed with water, dried over sodiumsulfate and concentrated. The residue was used as such in the nextreaction.

Step B

To a solution of crude2,6-dichloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile(2.32 g) in a 4:1 mixture THF/H₂O (63 ml) was added sodium periodate(5.01 g). The solution was stirred for 30 min. At room temperatureaqueous hydrochloric acid (1N, 5.5 ml) was added to the suspension. Thesolution was further stirred at room temperature for 6 hours then waterand diethyl ether were added and the phases were separated. The organiclayer was washed with water, dried over sodium sulfate and concentrated.The residue was used as such in the next reaction.

Step C

To a solution of crude 2,6-dichloro-4-(boronic acid)-benzonitrile (1.2g) in a 2:1 mixture THF/H₂O (27 ml) was added2-Bromo-3,3,3-trifluoro-propene (1.2 ml), potassium carbonate (1.54 g),and then1,3-bis(2,6-diisopropylphenyl)-imidazol-2-ylidene(1,4-naphthoquinone)palladium(438 mg). The reaction mixture was stirred at 60° C. for 3 hours. Thesolution was allowed to cool to room temperature and then filtered on aCelite pad. The filtrate was concentrated undervacuo and the residue wasthen dissolved with diethyl ether, extracted with water, dried overmagnesium sulfate and concentrated. The residue was purified bychromatography on silica gel to give2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g). ¹⁹F-NMR(CDCl₃, 75 MHz): −64.65 ppm.

Similarly,1-Chloro-3-trifluoromethyl-5-(1-trifluoromethyl-vinyl)-benzene wasobtained. ¹⁹F-NMR (CDCl₃, 75 MHz): −63.00 and -65.04 ppm.

Similarly, 1-Bromo-3-chloro-5-(1-trifluoromethyl-vinyl)-benzene wasobtained. ¹⁹F-NMR (CDCl₃, 75 MHz): −64.95 ppm.

Step D: Preparation of1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene

To a solution of 3-Trifluoromethoxy-benzeneboronic acid (2.5 g) in a 2:1mixture THF/H₂O (36 ml) was added 2-Bromo-3,3,3-trifluoro-propene (3.1ml), potassium carbonate (3.35 g), thenBis(triphenylphosphine)palladium(II) dichloride (169 mg). The reactionmixture was stirred at 60° C. for 7 hours. The solution was allowed tocool to room temperature then filtered on a Celite pad. The filtrate wasconcentrated in vacuo and the residue was then dissolved with ethylacetate, extracted with water, dried over magnesium sulfate andconcentrated. The residue was purified by chromatography on silica gelto give 1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene (1.23 g).¹⁹F-NMR (CDCl₃, 75 MHz): −57.87 ppm and −64.94 ppm.

Step E: Preparation of4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester

To a solution of 4-(hydroxyimino-methyl)-2-methyl-benzoic acidtert-butyl ester (1.47 g) in N,N-dimethylformamide (13 ml) was addedN-chlorosuccinimide (“NCS”) (832 mg). The reaction mixture was stirredat ambient temperature for 2 hours. More N-chlorosuccinimide (“NCS”)(850 mg) was added and the reaction mixture was stirred at ambienttemperature for 1 hour. A solution of2,6-Dichloro-4-(1-trifluoromethyl-vinyl)-benzonitrile (1.37 g) andtriethylamine (0.72 ml) in N,N-dimethylformamide (13 ml) was addeddropwise to the reaction mixture. The reaction mixture was stirred atambient temperature for 17 hours. Water and ethyl acetate were added andthe phases were separated. The organic layer was washed with water,dried over sodium sulfate and concentrated. The residue was purified bychromatography on silica gel to give4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester (0.902 g). ¹⁹F-NMR (CDCl₃, 75 MHz): −78.93 ppm.

Similarly,4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester was obtained when1-Bromo-3-chloro-5-(1-trifluoromethyl-vinyl)-benzene was used asreagent. ¹⁹F-NMR (CDCl₃, 75 MHz): −79.49 ppm.

Similarly,4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester was obtained when1-Chloro-3-trifluoromethyl-5-(1-trifluoromethyl-vinyl)-benzene was usedas reagent. ¹⁹F-NMR (CDCl₃, 75 MHz): −62.83 and -79.59 ppm.

Similarly,2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoicacid tert-butyl ester was obtained when1-Trifluoromethoxy-3-(1-trifluoromethyl-vinyl)-benzene was used asreagent. ¹⁹F-NMR (CDCl₃, 75 MHz): −57.87 ppm and -79.85 ppm.

Step F: Preparation of4-[5-(3,5-dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid

To a solution of4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester (763 mg) in dichloromethane (9 ml) was addedtrifluoromethyl acetic acid (“TFA”) (0.9 ml). The reaction mixture wasstirred at ambient temperature for 20 hours. Ethyl acetate was added andthe mixture was washed with water, dried over sodium sulfate andconcentrated to give4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid. ¹⁹F-NMR (CDCl₃, 75 MHz): −78.91 ppm.

Similarly,4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid was obtained when4-[5-(3-Bromo-5-chloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester was used as starting material. ¹⁹F-NMR (CDCl₃, 75MHz): −79.46 ppm.

Similarly,4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid was obtained when4-[5-(3-Chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester was used as starting material. ¹⁹F-NMR (CDCl₃, 75MHz): −62.84 and -79.56 ppm.

Similarly,2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoicacid was obtained when2-Methyl-4-[5-trifluoromethyl-5-(3-trifluoromethoxy-phenyl)-4,5-dihydro-isoxazol-3-yl]-benzoicacid tert-butyl ester was used as starting material. ¹⁹F-NMR (CDCl₃, 75MHz): −57.87 ppm and −79.83 ppm.

EXAMPLE 251-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-isoquinoline-4-carboxylicacid

The title product was prepared from 4-bromo-1-methyl-isoquinolinefollowing a similar route to that described in described in Example 21.

EXAMPLE 264-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This compound was prepared as described in WO 2005/085216.

EXAMPLE 272-Bromo-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This compound was prepared as described in WO 2009/080250.

EXAMPLE 284-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-naphthalene-1-carboxylicacid

This compound was prepared as described in WO 2010/025998.

EXAMPLE 292-Methyl-4-[5-(3-chloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This compound was prepared following a similar route to that describedin Example 24.

EXAMPLE 302-Methyl-4-[5-(3-chloro-5-bromo-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

This compound was prepared following a similar route to that describedin Example 24.

EXAMPLE 312-Methyl-4-[5-(3,5-dichloro-phenyl)-5-chlorodifluoromethyl-4,5-dihydro-isoxazol-3-yl]-benzoicacid

Step A: Preparation of4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester

To a solution of benzoic acid4-[chloro(hydroxyimino)methyl]-2-(trifluoromethyl) tert-butyl ester(prepared according to WO 2009/080250) (1.25 g) and1,3-dichloro-5-[1-(chloro-difluoro-methyl)-vinyl]-benzene (1.19 g)(prepared according to WO 2005/085216) in dichloromethane (30 ml)triethylamine (1.9 ml) was added. The reaction mixture was filtered overa plug of silica and concentrated to give (1.95 g)4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester (1.69 g) which was used in the following stepwithout any further purification.

Step B:4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid

To a solution of4-[5-(chloro-difluoro-methyl)-5-(3,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid tert-butyl ester (1.95 g) in dichloromethane (20 ml) was addedtrifluoromethyl acetic acid (“TFA”) (3 ml). The reaction mixture wasstirred at ambient temperature for 16 hours. The dichloromethane wasremoved by distillation. The residue was purified over silica gel(eluent: ethyl acetate/heptane gradient from 1:1 to 1:0) to give4-[5-(Chloro-difluoro-methyl)-5-(3,5-dichloro-phenyl)-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoicacid (1.37 g). ¹H-NMR (CDCl₃, 400 MHz): 8.10 (d, 1H), 7.65-7.45 (m, 5H),4.15 (m, 1H), 3.75 (d, 1H), 2.70 (s, 3H).

EXAMPLE 32 Preparation of (5{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-methyl-2-oxo-[1,2,3]oxathiazolidine-3-carboxylicacid carbamic acid ter-butyl ester (Compound F8) Step A: Preparation of(3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamicacid tert-butyl ester

Oxalyl chloride (0.9 ml) was added dropwise to a solution of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoicacid (0.9 g) in dichloromethane (20 ml) and 1 drop ofN,N-dimethylformamide and stirred at room temperature under nitrogen for6 hours. The mixture was concentrated and the residue was dissolved inacetonitrile (50 ml), treated with a solution of(3-amino-2-hydroxy-propyl)-carbamic acid ter-butyl ester (0.8 g) (J.Med. Chem. 1998, 41, 236-246), and a solution of triethylamine (0.9 ml)in acetonitrile (50 ml) and stirred for 16 hours under nitrogenatmosphere. The reaction mixture was concentrated and purified bychromatography on silica gel (eluent hexane/ethyl acetate 50:50) to givethe title compound (0.51 g). LCMS (Method G) 4.00 min, MH⁺590. ¹HNMR(CDCl₃, 400 MHz): 7.42-7.51 (m, 6H), 6.77 (m, 1H), 5.11 (t, 1H), 4.09(d, 1H), 3.86 (m, 1H), 3.80 (m, 1H), 3.72 (d, 1H), 3.67 (m, 1H), 3.48(m, 1H), 3.26 (m, 2H), 2.47 (s, 3H), 1.42 (s, 9H).

Step B: Preparation of (5{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-methyl-2-oxo-[1,2,3]oxathiazolidine-3-carboxylicacid carbamic acid tert-butyl ester

A solution of(3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamicacid tert-butyl ester (150 mg) in dichloromenthane (10 ml) was cooled to0° C., treated with pyridine (0.16 ml) and thionyl chloride (0.04 ml)and stirred for 2 hours. The mixture was diluted with dichloromenthane(50 ml), neutralized with 2N hydrochloric acid and washed with water (50ml). The organic layer was separated, dried over sodium sulfate andconcentrated. Purification by chromatography on silica gel (eluenthexane/ethyl acetate 40:60) gave the title compound (50 mg). LCMS(Method G) 4.29 min, MH⁺ 636. ¹HNMR (CDCl₃, 400 MHz): 7.13-7.59 (m, 6H),5.15 (m, 1H), 5.45 (m, 1H), 3.94-4.23 (m, 3H), 3.72 (m, 2H), 3.40 (m,1H), 2.45 (s, 3H), 1.51 (s, 9H).

EXAMPLE 33 Preparation of4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-[1,2,3]oxathiazolidin-5-ylmethyl)-benzamide(Compound F9) Step A: Preparation ofN-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide

A solution of(3{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoylamino}-2-hydroxy-propyl)-carbamicacid tert-butyl ester (0.2 g) in dichloromethane (10 ml) was cooled to0° C., treated with trifluoroacetic acid (0.5 ml) and stirred for 10 h.The reaction mixture was concentrated in vacuo and diluted withdichloromethane (50 ml), washed with saturated aqueous solution ofsodium bicarbonate (20 ml) and finally with water (2×20 ml). The organiclayer was separated, dried over sodium sulfate and concentrated to givethe title compound (0.13 g). LCMS (Method G) 2.84 min, MH⁺490. ¹HNMR(CDCl₃, 400 MHz): 8.05 (t, 1H), 7.81 (m, 1H), 7.80 (brs, 2H), 7.59 (m,4H), 7.48 (d, 1H), 4.36 (dd, 2H), 3.85 (m, 2H), 3.28 (m, 2H), 2.50 (m,1H), 2.37 (s, 3H).

Step B: Preparation of4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-oxo-[1,2,3]oxathiazolidin-5-ylmethyl)-benzamide

A solution ofN-(3-amino-2-hydroxy-propyl)-4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzamide(0.2 g) in dichloromethane (10 ml) was cooled to 0° C., treated withpyridine (0.32 ml) and thionyl chloride (0.06 ml), and stirred for 4hours. The mixture was diluted with dichloromethane (50 ml), neutralizedwith 2N hydrochloric acid, and washed with water (50 ml). The organiclayer was separated, dried over sodium sulfate and concentrated.Purification by chromatography on silica gel (eluent hexane/ethylacetate 40:60) gave the title compound (20 mg). LCMS (Method G) 3.88min, (M−H)⁻ 534. ¹HNMR (CDCl₃, 400 MHz): 7.45-7.52 (m, 6H), 6.50 (m,1H), 4.05 (d, 1H), 3.98 (m, 1H), 3.72 (d, 1H), 3.62 (m, 1H), 3.51 (m,3H), 2.46 (s, 3H).

EXAMPLE 34 Preparation of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(1-methyl-3-oxo-pyrazolodin-4-yl)-benzamide(Compound A4) Step A: Preparation of 4-amino-1-methyl-pyrazolidin-3-one

A solution of 4-benzyloxycarbonylamino-1-methyl-pyrazolidin-3-one (240mg, 1 mmol) (Tetrahedron 1998, 44(1), 3231-3240) in methanol (50 ml) wastreated with 10% Pd/C (24 mg) and hydrogenated at 3 bar pressure for 3hours. The suspension was filtered through Celite and the filtrate wasconcentrated under reduced pressure to give the title compound (110 mg).LCMS (Method G) 0.42 min, (M−H)⁺ 116. ¹HNMR (MeOD, 400 MHz): 2.96 (t,1H), 3.00 (s, 3H), 3.55 (m, 1H), 3.72 (t, 1H), 3.85 (bs, 2H).

Step B: Preparation of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(1-methyl-3-oxo-pyrazolodin-4-yl)-benzamide

Oxalyl chloride (0.18 ml) was added dropwise to a solution of4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-2-methylbenzoicacid (0.398 g) in dichloromethane (10 ml) and 1 drop ofN,N-dimethylformamide and stirred at room temperature under nitrogen for6 hours. The mixture was concentrated and the residue was dissolved indichloromethane (30 ml), treated with a solution of4-amino-1-methyl-pyrazolidin-3-one (0.11 g), a solution of triethylamine(0.5 ml) in tetrahydrofuran (20 ml), and stirred for 16 hours undernitrogen. The reaction mixture was concentrated and purified bychromatography on silica gel (eluent hexane/ethyl acetate 60:40) to give4-[5-(3,5-dichloro-phenyl)-5-methyl-4,5-dihydro-isoxazol-3-yl]-N-(1-methyl-3-oxo-pyrazolodin-4-yl)-benzamideas a solid compound which is a mixture of diasteromers (5 mg). ¹HNMR(CDCl₃): 2.42 (s, 3H), 3.01 (s, 3H), 3.55 (t, 1H), 3.71 (dd, 2H), 3.86(m, 1H), 4.08 (dd, 1H), 5.13 (m, 1H), 6.29 (br. d, 1H), 7.4-7.6 (m, 6H).

EXAMPLE 35 Preparation of Compounds of the Invention in Parallel

Following the general procedure described in Example 18, severalcompounds of formula (Ij) were prepared in parallel (compounds J1-J32 inTable J). Two diastereoisomers were separated in each case, named A andB in Table J.

EXAMPLE 36 Preparation of4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamideStep A:4-Acetyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide

To a suspension of 4-acetyl-2-methyl-benzoic acid (1 g, prepared asdescribed in WO2009001942) in dichloromethane (200 ml) anddimethylformamide (0.2 ml) under argon atmosphere at room temperature,was added dropwise oxalyl chloride (0.53 ml) then the resulting mixturewas stirred 1 hour at room temperature until the solid was dissolved.The solvent was removed in vacuo to afford crude4-acetyl-2-methyl-benzoic acid chloride. To a solution of(R)-4-amino-2-ethyl-isoxazolidin-3-one (1.64 g, Example 4, Step B) indry dichloromethane (10 ml) was added dropwise at room temperaturetriethylamine (5 ml). The solution of acid chloride in dichloromethane(5 ml) was added dropwise at room temperature. The resulting mixture wasallowed to stir 4 hours at room temperature, then quenched with water.The organic phase was washed with 1N aqueous hydrochloric acid solution.The organic layer was dried over sodium sulphate and the solvent wasremoved under reduced pressure to afford a residue, which was purifiedby crystallization from diethyl ether to give a beige solid (1 g). LCMS(Method A) 1.23 min, (M+H)+ 291. Chiral HPLC (method H) 30.18 min(98.99%), 33.62 min (1.01%). 1HNMR (CDCl₃, 400 MHz): 1.20 (t, 3H), 2.50(s, 3H), 2.60 (s, 3H), 3.65 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t,1H), 6.45 (bs, 1H), 7.50 (d, 1H), 7.70-7.90 (m, 2H).

Step B:4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide

To a solution of4-Acetyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide (1g) in 1,2-dichloroethane (5 ml) were added 3,5 dichloro 2,2,2trifuloroacetophenon (0.92 g), potassium carbonate (0.48 g), andtriethylamine (35 mg). The mixture was heated at 100° C. overnight,cooled to room temperature, then partitioned between ethyl acetate andwater. The aqueous layer was extracted twice with ethyl acetate and thecombined organic layers were dried over sodium sulphate and the solventsremoved in vacuo. The residuie was purified by column chromatography(ethyl acetate/cyclohexane) to obtain the title compound as a yellowsolid (1 g). LCMS (Method A) 2.02 min, (M+H)⁺515/517. ¹HNMR (CDCl₃, 400MHz): 83:17 mixture of diastereoisomers ((E) and (Z)). Major isomer:1.25 (t, 3H), 2.50 (s, 3H), 3.70 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H),5.0 (t, 1H), 6.35 (bd, 1H), 7.15-7.65 (m, 6H), Minor isomer: 1.25 (t,3H), 2.55 (s, 3H), 3.70 (m, 2H), 4.05 (m, 1H), 4.85 (m, 1H), 5.0 (t,1H), 6.40 (bd, 1H), 7.15-7.65 (m, 6H).

EXAMPLE 37 Asymmetric preparation of4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamideStep A: Catalyst preparation: 2,3,4,5,6-pentafluorophenyl-methylquininium bromide

A solution of 1-bromomethyl-2,3,4,5,6-pentafluorobenzene (0.52 g) andquinine (0.5 g) in toluene (9 ml) was heated at 80° C. for 18 hours. Thereaction mixture was poured in diethyl ether and then filtrate to affordthe title product as a white solid (0.90 g). M.p. 162-165° C.(decomposed). LCMS (method G) 1.08 min, M⁺ 505; ¹H NMR (400 MHz, CDCl₃)8.78 (d, 1H), 8.05 (d, 1H), 7.78 (d, 1H), 7.39 (dd, 1H), 7.18 (d, 1H),6.73 (m, 1H), 6.41 (d, 1H), 6.09 (d, 1H), 5.50 (m, 1H), 5.04 (d, 1H),4.98 (d, 1H), 4.70 (m, 1H), 4.63 (d, 1H), 3.98 (s, 3H), 3.97 (m, 1H),3.74 (m, 2H), 3.10 (m, 1H), 2.81 (m, 1H), 2.30 (m, 2H), 2.05 (m, 2H),1.41 (m, 1H). ¹⁹F NMR (376 MHz, CDCl₃) −132.67 (s, 1F), −146.60 (s, 2F),−158.28 (s, 2F).

Similarly were prepared the two catalysts 3,4,5-trimethoxybenzylquininium bromide and anthracenyl-methyl dihydroquininium bromide.

Step B:4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-N-(2-ethyl-3-oxo-isoxazolidin-4-yl)-benzamide

A pre-cooled solution of 5M sodium hydroxide (0.09 ml) was added to asolution of hydroxylamine (50% in water, 0.024 ml) at 5° C. (ice bath).The solution was stirred for 15 min at 5° C. then added to a vigorouslystirred solution of4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-N—((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-2-methyl-benzamide(100 mg) and anthracenyl-methyl quininium bromide (20 mg) (Step A) indichloroethane (1 ml) cooled in an ice-acetone bath. The mixture wasstirred rapidly at 0° C. for 4 hours. The reaction mixture was dilutedwith dichloromethane, passed through an isolute phase separatingcartridge and concentrated in vacuo to leave yellow oil. This residuewas purified by chromatography on silica gel (eluent: heptane/ethylacetate 5%) to give the title compound (9 mg). The product was analysedby chiral HPLC (method H): 18.7 min (42.5%), 19.6 min (24.2%), 21.4 min(8.5%), 22.8 min (24.8%).

Similarly, using 3,4,5-trimethoxybenzyl quininium bromide as a catalyst,the following ratio of isomers was obtained (38 mg): 18.5 min (14.9%),19.5 min (35.9%), 21.2 min (12.5%), 22.7 min (36.7%).

Similarly, using 2,3,4,5,6-pentafluorophenyl-methyl quininium bromide asa catalyst, the following ratio of isomers was obtained (23 mg): 18.6min (16.8%), 19.6 min (38.0%), 21.3 min (9.2%), 22.7 min (36.0%).

TABLE A Compounds of formula (Ia): (Ia)

LCMS mass Comp Meth- RT spec- No. R⁵ Y¹ Y² Y³ Y⁴ R² od (min) trum A1 MeCH₂ S S CH₂ H F 2.20 519/ 521 A2 Me CH₂ S(O) O CH₂ H F 2.04 519/ 521 A3Me CH₂ O N—Et CH₂ H E 2.02 516/ 518 A4 Me CH₂ N—Me N—H C(O) H NMR seeExample 34

TABLE B Compounds of formula (Ib): (Ib)

Comp LCMS mass No. R⁵ G¹ R⁹ Method RT (min) spectrum B1 Me O H F 1.99500/502 B2 Me O CH₃ A 1.99 516/518 B3 Me O propargyl A 2.06 538/540 B4Me O benzyl F 2.17 590/592 B5 Me O 2,2,2-trifluoroethyl F 2.11 582/584B6 Me O CH₂CH₃ F 2.05 528/530 B7 Me O 2-methoxyethyl F 2.02 558/560 B8Me O n-butyl F 2.14 556/558 B9 Me O 2-hydroxyethyl F 1.94 544/546 B10 MeO thietan-3yl F 2.13 572/574 B11 Me O cyclobutyl F 2.16 554/556 B12 Me Ooxetan-3yl F 2.06 556/558 B13 Me O 3-methyl-but-2-enyl J 2.04 570.29 B14Me O 4-nitro-benzyl J 1.90 637.28 B15 Me O 1,1,1-trifluoropropan-3-yl J1.96 598.24 B16 Me O 4-fluoro-benzyl J 2.04 610.27 B17 Me O1,1,1-trifluorobutan-4-yl J 2.01 612.27 B18 Me O 2-cyanoethyl J 1.80555.24 B19 Me O 2,6-difluoro-benzyl J 2.04 628.29 B20 Me Ocyclopropylmethyl J 1.95 556.3  B21 Me O 2-[1,3]dioxan-2-yl-ethyl J 1.88616.3  B22 Me O 5-trifluoromethyl-furan-2- J 2.07 650.24 ylmethyl B23 MeO 2,5-dimethyl-2H- J 1.85 611.32 [1,2,3]triazol-4-ylmethyl B24 Me Ocyclobutylmethyl J 2.05 570.29 B25 Me O 3-cyanopropyl J 1.82 569.27 B26Me O tetrahydro-pyran-2- J 1.96 600.33 ylmethyl B27 Me O 3-phenyl-propylJ 2.14 620.33 B28 Me O but-2-ynyl J 1.92 554.25 B29 Me Ocyclohexylmethyl J 2.18 598.34 B30 Me O (propan-2-one J 1.93 587.26O-methyl-oxime)-1-yl

TABLE C Compounds of formula (Ic): (Ic)

Comp LCMS mass No. R⁴ A³ R⁹ Method RT (min) spectrum C1 3,4,5-trichloro-CH ethyl F 2.09 562/564/ phenyl 566 C2 3,5-dichloro-4- CH ethyl F 2.09605/607/ bromo-phenyl 609 C3 3,5-dichloro-4- CH ethyl F 2.04 546/548fluoro-phenyl C4 3,5-trifluoro- CH ethyl F 2.15 630/632 methyl-4-chloro-phenyl C5 3-chloro-5- CH ethyl F 1.99 512/514 fluoro-phenyl C63,5-dichloro- N 2,2,2- F 2.13 583/585 phenyl trifluoroethyl C73,5-dichloro- N ethyl F 2.03 529/531 phenyl C8 3,4,5-trichloro- CH2,2,2- F 2.18 616/618/ phenyl trifluoroethyl 620 C9 3,5-dichloro-4- CH2,2,2- F 2.13 600/602 fluoro-phenyl trifluoroethyl

TABLE D Compounds of formula (Id): (Id)

LCMS RT Comp No. R⁴ R⁹ Method (min) mass spectrum D13,5-trichloro-phenyl ethyl D 2.21 578/580

TABLE E Compounds of formula (Ie): (Ie)

Comp No. R⁵ G¹ R⁹ LCMS Method RT (min) mass spectrum E1 Me O CH₃ F 1.98514/516 E2 Me O CH₂CH₃ F 2.06 528/530

TABLE F Compounds of formula (If): (If)

LCMS Comp No. R⁵ Y¹ Y² Y³ Y⁴ Method RT (min) mass spectrum F1 Me CH₂ CH₂N—CH₂Ph O F 2.20 590/591 F2 Me CH₂ CH₂ N—CH₃ O F 1.80 514/516 F3 Me CH₂C(O) N—CH₂CH₃ O F 2.02 542/544 F4 Me CH₂ C(O) N—CH₂CF₃ O F 2.11 596/598F5 Me CH₂ O S(O) O G 4.07 536 F6 Me CH₂ CH₂ N-(4-methoxy- SO₂ F 2.02654/655 phenyl) F7 Me CH₂ CH₂ N-(2,2,2- SO₂ F 2.41 630/632trifluoroethyl) F8 Me CH₂ N—COOtBu S(O) O G 4.29 636 F9 Me CH₂ NH S(O) OG 3.88 534

TABLE G Compounds of formula (Ig): (Ig)

Stereo- Stereo- Comp chemistry chemistry HPLC RT mass No. at C-5 at C-4′R⁹ Method (min) spectrum G1 (S) (R) ethyl H 21.3  — G2 (R) (R) ethyl H19.8  — G3 (S) (S) ethyl H 21.1  — G4 (R) (S) ethyl H 17.1  — G5 (S) (R)2,2,2- F  2.25 582/584 trifluoroethyl G6 (S) (R) 2,2- F  2.09 564/566difluoroethyl

TABLE H Compounds of formula (Ih): (Ih)

      Comp No.

        R⁴         R³         R⁹       LCMS Method       RT (min)        MH⁺ H1

CF₃ CH₂CH₃ J 1.78 546.31 H2

CF₃ CH₂CH₃ J 1.85 530.64 H3

CF₃ CH₂CH₃ J 1.92 567.25 H4

CF₃ CH₂CH₃ J 1.85 517.24 H5

CF₃ CH₂CH₃ J 1.94 556.27 H6

CF₃ CH₂CH₃ J 1.75 555.26 H7

CF₃ CH₂CH₃ J 2   567.25 H8

CF₃ CH₂CH₃ J 1.82 516.26 H9

CF₃ CH₂CH₃ J 1.9  594.14 H10

CF₃ CH₂CH₃ J 1.97 566.27 H11

CF₃ CH₂CH₃ J 1.89 564.28 H12

CF₃ CH₂CH₃ J 1.89 574.19 H13

CF₃ CH₂CH₃ J 1.9  546.23 H14

CF₃ CH₂CF₃ J 1.95 677.26 H15

CF₃ CH₂CF₃ J 1.88 600.28 H16

CF₃ CH₂CF₃ J 1.95 585.24 H17

CF₃ CH₂CF₃ J 2.02 621.25 H18

CF₃ CH₂CF₃ J 1.95 571.22 H19

CF₃ CH₂CF₃ J 2.03 610.25 H20

CF₃ CH₂CF₃ J 1.85 609.21 H21

CF₃ CH₂CF₃ J 1.93 569.83 H22

CF₃ CH₂CF₃ J 1.99 648.15 H23

CF₃ CH₂CF₃ J 2.05 620.25 H24

CF₃ CH₂CF₃ J 1.98 618.26 H25

CF₃ CH₂CF₃ J 1.98 628.2  H26

CClF₂ CH₂CF₃ J 2   600.22

TABLE J Compounds of formula (Ij): (Ij)

      Comp No.

        R⁴         R³         Diastereoisomer       LCMS Method       RT(min)         MH⁺ J1

CClF₂ A J 1.82 537.23 J2

CClF₂ B J 1.88 537.14 J3

CF₃ A J 1.9  555.13 J4

CF₃ B J 1.95 555.15 J5

CF₃ A J 1.82 555.22 J6

CF₃ B J 1.86 555.22 J7

CF₃ A J 1.91 599.13 J8

CF₃ B J 1.95 599.17 J9

CF₃ A J 1.9  647.07 J10

CF₃ B J 1.95 647.09 J11

CF₃ A J 1.82 565.14 J12

CF₃ B J 1.86 565.14 J13

CF₃ A J 1.82 539.19 J14

CF₃ B J 1.86 539.16 J15

CF₃ A J 1.75 522.19 J16

CF₃ B J 1.78 522.19 J17

CF₃ A J 1.82 585.12 J18

CF₃ B J 1.87 585.09 J19

CF₃ A J 1.9  557.15 J20

CF₃ B J 1.94 557.2 J21

CF₃ A J 1.86 547.21 J22

CF₃ B J 1.92 547.2  J23

CF₃ A J 1.68 546.18 J24

CF₃ B J 1.72 546.18 J25

CF₃ A J 1.77 507.16 J26

CF₃ B J 1.81 507.15 J27

CF₃ A J 1.66 521.26 J28

CF₃ B J 1.71 520.72 J29

CF₃ A J 1.85 589.24 J30

CF₃ B J 1.89 589.23 J31

CF₃ A J 1.86 575.16 J32

CF₃ B J 1.91 575.15

BIOLOGICAL EXAMPLES

This Example illustrates the pesticidal/insecticidal properties ofcompounds of formula (I). Tests were performed as follows:

Spodoptera littoralis (Egyptian Cotton Leafworm):

Cotton leaf discs were placed on agar in a 24-well microtiter plate andsprayed with test solutions at an application rate of 200 ppm. Afterdrying, the leaf discs were infested with 5 L1 larvae. The samples werechecked for mortality, feeding behavior, and growth regulation 3 daysafter treatment (DAT).

The following compounds gave at least 80% control of Spodopteralittoralis: A1, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12,C1, C2, C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3,G5, G6, H1, H2, H3, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15,H16, H18, H19, H20, H21, H22, H23, H24, H25, and H26.

Heliothis virescens (Tobacco Budworm):

Eggs (0-24 h old) were placed in 24-well microtiter plate on artificialdiet and treated with test solutions at an application rate of 200 ppm(concentration in well 18 ppm) by pipetting. After an incubation periodof 4 days, samples were checked for egg mortality, larval mortality, andgrowth regulation.

The following compounds gave at least 80% control of Heliothisvirescens: A1, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B12, C1, C2,C3, C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6,H1, H2, H3, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18,H19, H20, H21, H22, H23, H24, H25, H26, J10, and J16.

Plutella xylostella (Diamond Back Moth):

24-well microtiter plate (MTP) with artificial diet was treated withtest solutions at an application rate of 200 ppm (concentration in well18 ppm) by pipetting. After drying, the MTP's were infested with L2larvae (7-12 per well). After an incubation period of 6 days, sampleswere checked for larval mortality and growth regulation.

The following compounds gave at least 80% control of Plutellaxylostella:

A1, A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3,C4, C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1,H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18, H19, H20,H21, H22, H23, H24, H25, H26, J1, J10, and J13.

Diabrotica balteata (Corn Root Worm):

A 24-well microtiter plate (MTP) with artificial diet was treated withtest solutions at an application rate of 200 ppm (concentration in well18 ppm) by pipetting. After drying, the MTP's were infested with L2larvae (6-10 per well). After an incubation period of 5 days, sampleswere checked for larval mortality and growth regulation.

The following compounds gave at least 80% control of Diabroticabalteata:

A1, A3, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4,C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H5,H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H18, H19, H20, H21,H22, H23, H24, H25, H26, J4, and J20.

Myzus persicae (Green peach aphid), systemic test: Roots of peaseedlings, infested with an aphid population of mixed ages, are placeddirectly in the test solutions at an application rate of 12.5 ppm. 6days after introduction, samples are checked for mortality and specialeffects on the plant. The following compounds gave at least 80% controlof Myzus persicae: A3, B2, B3, B5, B6, B7, B8, B11, B12, C1, C2, C3,C4,C5, C6, C7, D1, E1, E2, G1, G3, G5, G6, H1, H5, H6, H9, H10, H11, H12,H13, H14, H18, H19, H20, H24, H25, and H26.

Thrips tabaci (Onion Thrips):

Sunflower leaf discs were placed on agar in a 24-well microtiter plateand sprayed with test solutions at an application rate of 200 ppm. Afterdrying, the leaf discs were infested with an aphid population of mixedages. After an incubation period of 7 days, samples were checked formortality.

The following compounds gave at least 80% control of Thrips tabaci:

A1, A3, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4,C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, G1, G3, G5, G6, H1, H2, H3,H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H18, H19, H20, H21,H22, H23, H24, H25, H26, J3, J6, J8, J10, J19, and J20.

Tetranychus urticae (Two-Spotted Spider Mite):

Bean leaf discs on agar in 24-well microtiter plates were sprayed withtest solutions at an application rate of 200 ppm. After drying, the leafdiscs are infested with mite populations of mixed ages. 8 days later,discs are checked for egg mortality, larval mortality, and adultmortality.

The following compounds gave at least 80% control of Tetranychusurticae:

A3, B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, C1, C2, C3, C4,C5, C6, C7, D1, E1, E2, F1, F2, F3, F4, F5, F6, G1, G3, G5, G6, H1, H2,H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H18, H19, H20, H21,H22, H23, H24, H25, and H26.

1. A compound of formula (Int-I)

wherein A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen; G¹ is oxygen or sulfur; L is a single bond or C₁-C₈alkylene;R¹ is hydrogen, C₁-C₅alkyl, C₁-C₅alkylcarbonyl-, C₁-C₅alkoxy,C₁-C₅alkoxy-C₁-C₈alkyl or C₁-C₅alkoxycarbonyl-; R² is hydrogen,C₁-C₅haloalkyl or C₁-C₅alkyl; each R⁵ is independently halogen, cyano,nitro, C₁-C₅alkyl, C₃-C₅cycloalkyl, C₁-C₈haloalkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, C₁-C₅alkoxy,C₁-C₅haloalkoxy, C₁-C₅alkoxycarbonyl-, or two R⁵ on adjacent carbonatoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge; Y¹is CR⁷R⁸, Y² is O, Y³ is N—R⁹ and Y⁴ is C═O; each R⁷ and R⁸ isindependently hydrogen, halogen, C₁-C₈alkyl, or C₁-C₈haloalkyl; each R⁹is independently hydrogen, cyano, cyano-C₁-C₅alkyl, C₁-C₅alkyl,C₁-C₈haloalkyl, C₃-C₅cycloalkyl, C₃-C₅cycloalkyl where one carbon atomis replaced by O, S, S(O) or SO₂, or C₃-C₈cycloalkyl-C₁-C₈alkyl,C₃-C₈cycloalkyl-C₁-C₈alkyl where one carbon atom in the cycloalkyl groupis replaced by O, S, S(O) or SO₂, or C₃-C₅cycloalkyl-C₁-C₈haloalkyl,C₁-C₅hydroxyalkyl, C₁-C₅alkoxy-C₁-C₅alkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₈alkynyl, C₂-C₅haloalkynyl, phenyl, phenylsubstituted by one to three R¹⁰, phenyl-C₁-C₄alkyl, phenyl-C₁-C₄alkylwherein the phenyl moiety is substituted by one to three R¹⁰, 5-6membered heteroaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkylwherein the heteroaryl moiety is substituted by one to three R¹⁰,C₁-C₄alkyl-(C₁-C₄alkyl-O—N═)C—CH₂—; each R¹⁰ is independently halogen,cyano, nitro, C₁-C₅alkyl, C₁-C₅haloalkyl, C₁-C₈alkoxy, orC₁-C₅haloalkoxy; and X^(B) is a leaving group, or X^(B) is cyano,formyl, CH═N—OH or acetyl; or a salt or N-oxide thereof; or a compoundof formula (Int-II)

wherein A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen; G¹ is oxygen or sulfur; L is a single bond or C₁-C₈alkylene;R¹ is hydrogen, C₁-C₅alkyl, C₁-C₅alkylcarbonyl-, C₁-C₅alkoxy,C₁-C₅alkoxy-C₁-C₈alkyl or C₁-C₅alkoxycarbonyl-; R² is hydrogen,C₁-C₅haloalkyl or C₁-C₅alkyl; each R⁵ is independently halogen, cyano,nitro, C₁-C₅alkyl, C₃-C₅cycloalkyl, C₁-C₈haloalkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, C₁-C₅alkoxy,C₁-C₈haloalkoxy, C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbonatoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge; Y¹is CR⁷R⁸, Y² is O, Y³ is N—R⁹ and Y⁴ is C═O; each R⁷ and R⁸ isindependently hydrogen, halogen, C₁-C₈alkyl, or C₁-C₈haloalkyl; each R⁹is independently hydrogen, cyano, cyano-C₁-C₅alkyl, C₁-C₅alkyl,C₁-C₈haloalkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl where one carbon atomis replaced by O, S, S(O) or SO₂, or C₃-C₅cycloalkyl-C₁-C₈alkyl,C₃-C₅cycloalkyl-C₁-C₈alkyl where one carbon atom in the cycloalkyl groupis replaced by O, S, S(O) or SO₂, or C₃-C₅cycloalkyl-C₁-C₈haloalkyl,C₁-C₅hydroxyalkyl, C₁-C₅alkoxy-C₁-C₅alkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, phenyl, phenylsubstituted by one to three R¹⁰, phenyl-C₁-C₄alkyl, phenyl-C₁-C₄alkylwherein the phenyl moiety is substituted by one to three R¹⁰, 5-6membered heteroaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkylwherein the heteroaryl moiety is substituted by one to three R¹⁰,C₁-C₄alkyl-(C₁-C₄alkyl-O—N═)C—CH₂—; each R¹⁰ is independently halogen,cyano, nitro, C₁-C₅alkyl, C₁-C₅haloalkyl, C₁-C₈alkoxy, orC₁-C₅haloalkoxy; and X^(C) is CH₂-halogen, CH═C(R³)R⁴, or CH₂C(OH)(R³)R⁴wherein R³ is C₁-C₅haloalkyl; R⁴ is aryl or aryl substituted by one tothree R⁶, or R⁴ is heterocyclyl or heterocyclyl substituted by one tothree R⁶; and each R⁶ is independently halogen, cyano, nitro,C₁-C₅alkyl, C₁-C₅haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy; or a saltor N-oxide thereof.
 2. A method of controlling at least one parasiticinvertebrate pest in or on an animal, the method comprising:administering to the animal a compound of formula (I)

wherein A¹, A², A³ and A⁴ are independently of one another C—H, C—R⁵, ornitrogen; G¹ is oxygen or sulfur; L is a single bond or C₁-C₈alkylene;R¹ is hydrogen, C₁-C₅alkyl, C₁-C₅alkylcarbonyl-, C₁-C₅alkoxy,C₁-C₅alkoxy-C₁-C₈alkyl or C₁-C₅alkoxycarbonyl-; R² is hydrogen,C₁-C₅haloalkyl or C₁-C₅alkyl; R³ is C₁-C₈haloalkyl; R⁴ is aryl or arylsubstituted by one to three R⁶, or R⁴ is heterocyclyl or heterocyclylsubstituted by one to three R⁶; each R⁵ is independently halogen, cyano,nitro, C₁-C₈alkyl, C₃-C₈cycloalkyl, C₁-C₈haloalkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₅alkynyl, C₂-C₅haloalkynyl, C₁-C₅alkoxy,C₁-C₈haloalkoxy, C₁-C₈alkoxycarbonyl-, or two R⁵ on adjacent carbonatoms together form a —CH═CH—CH═CH— bridge or a —N═CH—CH═CH— bridge;each R⁶ is independently halogen, cyano, nitro, C₁-C₅alkyl,C₁-C₅haloalkyl, C₁-C₈alkoxy, or C₁-C₈haloalkoxy; Y¹ is CR⁷R⁸, Y² is O,Y³ is N—R⁹ and Y⁴ is C═O; each R⁷ and R⁸ is independently hydrogen,halogen, C₁-C₅alkyl, or C₁-C₅haloalkyl; each R⁹ is independentlyhydrogen, cyano, cyano-C₁-C₅alkyl, C₁-C₅alkyl, C₁-C₈haloalkyl,C₃-C₅cycloalkyl, C₃-C₅cycloalkyl where one carbon atom is replaced by O,S, S(O) or SO₂, or C₃-C₅cycloalkyl-C₁-C₈alkyl,C₃-C₅cycloalkyl-C₁-C₈alkyl where one carbon atom in the cycloalkyl groupis replaced by O, S, S(O) or SO₂, or C₃-C₈cycloalkyl-C₁-C₈haloalkyl,C₁-C₅hydroxyalkyl, C₁-C₅alkoxy-C₁-C₅alkyl, C₂-C₅alkenyl,C₂-C₅haloalkenyl, C₂-C₈alkynyl, C₂-C₈haloalkynyl, phenyl, phenylsubstituted by one to three R¹⁰, phenyl-C₁-C₄alkyl, phenyl-C₁-C₄alkylwherein the phenyl moiety is substituted by one to three R¹⁰, 5-6membered heteroaryl-C₁-C₄alkyl or 5-6 membered heteroaryl-C₁-C₄alkylwherein the heteroaryl moiety is substituted by one to three R¹⁰,C₁-C₄alkyl-(C₁-C₄alkyl-O—N═)C—CH₂—; each R¹⁰ is independently halogen,cyano, nitro, C₁-C₅alkyl, C₁-C₅haloalkyl, C₁-C₈alkoxy, orC₁-C₅haloalkoxy; or a salt or N-oxide thereof.
 3. The method of claim 2,wherein the compound is a compound of formula (Ia.E):


4. The method of claim 2 wherein R⁹ is hydrogen, cyano-C₁-C₅alkyl,C₁-C₅alkyl, C₃-C₈cycloalkyl, C₃-C₅cycloalkyl where one carbon atom inthe cycloalkyl group is replaced by O, S, S(O) or SO₂, orC₁-C₈haloalkyl, C₁-C₈hydroxyalkyl, C₂-C₅alkenyl, C₂-C₅alkynyl,phenyl-C₁-C₄alkyl or phenyl-C₁-C₄alkyl wherein the phenyl moiety issubstituted by one to three R¹⁰, 5-6 membered heteroaryl-C₁-C₄alkyl or5-6 membered heteroaryl-C₁-C₄alkyl wherein the heteroaryl moiety issubstituted by one to three R¹⁰, and wherein the heteroaryl is pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, furanyl, thiophenyl,oxazolyl, isoxazolyl or thiazolyl.
 5. The method of claim 2, wherein theanimal is selected from the group consisting of a cow, a pig, a sheep, agoat, a horse, a donkey, a dog and a cat.
 6. The method of claim 2,wherein the pest is selected from the group consisting of a nematode, atrematode, a cestode, a fly, a mite, a tick, a louse, a flea, a true bugand a maggot.
 7. The method of claim 2, wherein administering isselected from the group consisting of an oral administration, aparenteral administration, and an external administration.
 8. A methodof controlling at least one parasitic invertebrate pest in or on ananimal, the method comprising: administering to the animal a compound offormula (I)